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

D. and colleagues situate their study within growing clinical and patient-reported evidence that low doses of psilocybin and related 5-HT2A agonists can reduce disease burden in headache disorders. Patient-led practices in cluster headache have popularised a pulsed dosing paradigm (several administrations in close succession) that patients report yields durable reductions in attack frequency; this approach has not been formally tested in migraine. The authors also note prior work from their group showing that a single low oral dose of psilocybin reduced migraine frequency in a small pilot study, but that trial used an inert placebo and measured effects only over a short interval, leaving questions about dose scheduling and placebo effects unresolved. The present study aimed to explore whether a pulsed two-dose regimen of low-dose psilocybin (two doses 1 week apart) produces greater magnitude or duration of migraine prevention than a single dose, and to assess blinding integrity using an active placebo (diphenhydramine 25 mg). The primary outcome was change in migraine days per week in the 2 weeks after the dosing regimen, with additional follow-up to 8 weeks to assess duration of effect. The work is presented as an exploratory, randomised, double-blind, placebo-controlled, parallel group clinical trial intended to inform future, larger studies.

The study was a single-site, randomised, double-blind, placebo-controlled, parallel group trial. Adults aged 21–65 years with migraine (with or without aura) meeting International Classification of Headache Disorders criteria and reporting at least two migraine days per week were eligible. Key exclusions included serious medical or psychiatric conditions, recent psychedelic use (within 3 months), and current serotonergic antidepressant use unless safely discontinued at least 6 weeks prior. Triptans were permitted with restrictions on frequency and timing relative to test days. Urine drug screens and pregnancy tests were required prior to dosing. Regulatory approvals and an Investigational New Drug application were obtained and the trial was registered. Participants completed two supervised dosing sessions separated by 7 (±2) days and were randomised to one of three sequences: diph-diph (placebo on both days; zero psilocybin doses), diph-psi (placebo then psilocybin; one psilocybin dose), or psi-psi (psilocybin on both days; two psilocybin doses). Psilocybin dose was 10 mg per session and the active placebo was diphenhydramine 25 mg administered in identical capsules. The authors planned to enrol six participants per arm based on prior experience; no formal power calculation was performed. The primary outcome was change in migraine days per week over the 2 weeks following completion of the dosing sessions, collected via daily headache diaries that began 2 weeks prior to the first dosing and continued for 8 weeks after the second session. Secondary outcomes included migraine attacks per week, attack duration, pain intensity (0–3 numeric rating scale), associated symptom severity (0–3 NRS), acute vital sign changes, general drug effects (0–4 NRS), psychedelic effects (5D-ASC scale), drug confidence (blinding integrity; 0–6 NRS), and incidence of adverse events. Statistical analyses used nonparametric methods because of small sample size and deviations from parametric assumptions: Kruskal–Wallis and Mann–Whitney U tests for between-group comparisons, a ranked mixed-effects nonparametric approach for repeated measures (with analysis of variance-type statistics, ATS), Fisher exact test for responder rates (50% reduction), and Spearman correlations for associations between subjective measures and clinical outcomes.

From 220 prescreened individuals, 25 were enrolled between September 2021 and August 2023; seven did not take part and two withdrew after the first dosing session (one for travel restrictions related to SARS-CoV-2 Omicron, one for anxiety). Due to insufficient headache diary data for two participants, 16 participants were included in the final analysis: six in diph-diph, five in diph-psi, and five in psi-psi. The sample comprised 2 males and 14 females; other demographic details (for example age distribution) are not clearly reported in the extracted text. Headache diary outcomes: Both active psilocybin groups (diph-psi and psi-psi) showed reductions of about two migraine days per week (~60% reduction) sustained over the 8-week follow-up, while the diph-diph group showed a smaller numerical reduction (up to ~40%). However, differences among groups did not reach statistical significance over 2, 4, or 8 weeks. The proportion of participants achieving a 50% reduction in migraine days (the 50% response rate) differed numerically among groups: diph-diph had 17%, 33%, and 33% at 2, 4, and 8 weeks; diph-psi had 80% at 2, 4, and 8 weeks; psi-psi had 80%, 60%, and 80% at 2, 4, and 8 weeks. The difference in 50% response rate over 2 weeks approached significance. Other attack features: A significant group effect was observed for attack duration at 2 weeks [Χ2(2) = 8.46, p = 0.015] and 4 weeks [Χ2(2) = 9.70, p = 0.008]; the diph-psi arm showed reduced duration but had a substantially higher baseline duration compared with the other groups. There were no significant group differences in attack frequency or pain intensity over 2, 4, or 8 weeks. Photophobia intensity over 8 weeks showed a group effect [Χ2(2) = 7.39, p = 0.025] with reduction in the diph-diph group. Acute effects during dosing sessions: No significant group × time × day interactions were found for vital signs. Nausea ratings during sessions differed by group [group × time × day effect for nausea, p < 0.001], with nausea more common after psilocybin. Psychedelic effects measured by the 5D-ASC showed significant group × day interaction for total percent maximum score (ATS p = 0.048) and for several dimensions: oceanic boundlessness (p = 0.011), visionary restructuralization (p = 0.019), and auditory alteration (p < 0.001). There were no significant correlations between change in migraine frequency and total 5D-ASC score (Spearman r s = -0.365, p = 0.299) or overall drug effects rating (r s = -0.284, p = 0.420). Blinding integrity (drug confidence): A significant group × day interaction was observed for confidence that one had received psilocybin (ATS p = 0.025). In the diph-psi group (participants exposed to both drugs across days), psilocybin confidence increased markedly from day 1 to day 2 (2.2 to 5.6; p < 0.001), whereas no significant day-to-day change was seen in the diph-diph or psi-psi groups. There was no correlation between confidence ratings and change in migraine frequency over 2 weeks. Adverse events: No serious or unexpected adverse events occurred. The most frequent AEs during dosing were fatigue and nausea; nausea was significantly more common with psilocybin (p = 0.002). In the 24 hours after dosing, fatigue and migraine were most commonly reported; fatigue was significantly more common after psilocybin (p = 0.008). All adverse events were self-limiting or managed with usual abortive therapy. No persistent physical or neuropsychological changes were reported up to 6 months.

D. and colleagues interpret the findings as showing no statistically significant advantage of a pulsed two-dose psilocybin regimen over a single low dose for migraine prevention in this exploratory sample, and note that the placebo (diphenhydramine) group experienced substantial reductions in migraine frequency as well. The authors emphasise that although the active psilocybin arms appeared to separate from placebo in the first weeks after dosing with large effect sizes, the small sample size can produce unstable and potentially inflated effect estimates, and the primary outcome did not achieve statistical significance across the analysed intervals. The use of an active placebo was presented as an important methodological step to probe non-drug effects, expectation, and blinding integrity. Diphenhydramine partially mimicked some acute subjective effects but did not perfectly substitute for psilocybin; when participants received both drugs, they were more likely to differentiate them, highlighting risks of unblinding in crossover or within-subject designs. The authors discuss the substantial role of placebo response in migraine trials and psychedelic research and note that heightened public expectations about psychedelics and the absence of additional procedures such as psychotherapy (psychedelic-assisted psychotherapy) in this study may have affected observed outcomes. The lack of correlation between acute psychedelic effects (5D-ASC) and clinical migraine outcomes is consistent with prior observations in headache populations, where low or sub-psychedelic doses have produced benefit in some reports. Limitations acknowledged by the authors include the small sample size and resulting limited statistical power and generalisability; inclusion of both episodic and chronic migraine in the same sample (subtypes usually studied separately); absence of a formal measure of research staff blinding; and lack of a pre-procedure measure of participant expectation. The authors also acknowledge that diphenhydramine 25 mg may not be the ideal active comparator to reproduce psilocybin's acute experiential profile and suggest other agents (for example THC or dextromethorphan) might be explored. Strengths noted include the randomised, double-blind, placebo-controlled parallel group design. The authors recommend that future larger trials incorporate suitable active placebos, prospective measures of expectation and blinding integrity, careful selection of dose and dosing frequency tailored to migraine, and involvement of headache specialists in study design and conduct to better separate drug and non-drug effects and preserve clinical relevance.

The authors conclude that this exploratory trial did not demonstrate a statistically significant difference in migraine reduction between a single low dose and a two-dose pulse of psilocybin. The clinically meaningful reductions observed in the diphenhydramine placebo group indicate that non-drug effects, most likely placebo responses, contributed to the observed outcomes. D. and colleagues state that further rigorous studies are needed to determine whether pulsed psilocybin dosing can offer additional benefits in amplitude or duration of effect, and that future trials should use adequate active placebos, include measures of expectation and blinding, and be carefully designed to fit migraine disease characteristics and treatment standards.