In an exploratory randomised, double‑blind trial in adults with frequent migraine, single or two‑dose psilocybin produced reductions in migraine frequency similar to an active diphenhydramine placebo and no serious adverse events were observed. Incomplete blinding and nonsignificant between‑group differences despite large effect sizes in psilocybin arms indicate the need for larger, better‑controlled trials with headache‑specialist input to separate drug and non‑drug effects.
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Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H. et al. · Headache (2022)
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); Χ 2 (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.
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.
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.
Preliminary research suggests that a single low dose of psilocybin reduces migraine frequency by about half, but more research is needed to verify this and learn more about how psilocybin might treat migraine. In this follow-up clinical trial, the idea of giving two doses of psilocybin in the space of 1 week instead of just one dose of psilocybin or a placebo (diphenhydramine) to improve outcomes was tested. There was no difference between one or two doses of psilocybin, and interestingly, even the placebo group had a good response, which urges us to carefully consider how much of the improvement actually came from psilocybin.
the acute subjective effects of psilocybin (10 mg) and allow for quantification of placebo effects. This report is the primary analysis of these data.
The materials and methods for this study are similar to those described in our pilot psilocybin migraine and cluster headache studies.Details for the present study are described below.
This study was registered on clinicaltrials.gov (NCT04218539) and received approvals from the Human Studies Subcommittee of Veterans Affairs Connecticut Healthcare System (VACHS) (West Haven, CT) and the Human Investigations Committee of Yale University (New Haven, CT). The study was conducted under an approved Investigational New Drug application (#124874) with the US Food and Drug Administration (FDA). On the day that a participant was assigned to receive placebo, the VACHS Investigational Drug Service (i.e., research pharmacy) split one 25 mg diphenhydramine tablet in half and encapsulated each half in a blue gelatin capsule (Letco Medical; Decatur, AL) backfilled with MCC (Fagron; St. Paul, MN). Gel capsules were identical; therefore, on dosing sessions, two capsules of diphenhydramine (totaling 25 mg) or psilocybin (totaling 10 mg) were administered that appeared identical to study participants and staff.
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Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H. et al. · Neurotherapeutics (2021)
Sewell, R. A. · Neurology (2006)
Madsen, M. K., Petersen, A. S., Stenbæk, D. S. et al. · Headache (2024)
Schindler, E. A. D., Sewell, R. A., Gottschalk, C. H. et al. · Journal of the Neurological Sciences (2024)
Schindler, E. A. D., Gottschalk, C. H., Weil, M. J. et al. · Journal of Psychoactive Drugs (2015)
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D’Souza, D. C., Syed, S. A., Safi-Aghdam, H. et al. · Neuropsychopharmacology (2022)
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.
Study participants were required to be aged 21 to 65 years (inclusive) and free from serious medical or psychiatric conditions (e.g., cardiovascular disease, cerebrovascular disease, active substance use disorder, psychotic or manic disorder). All met criteria for migraine with or without aura using the International Classification of Headache Disorders, 3rd edition, beta version.Requiring a minimum frequency of 2 days per week allowed patients with episodic and chronic migraine to participate. Due to the potential for serotonergic antidepressants (e.g., fluoxetine, nortriptyline) to interfere with psilocybin's effects, these drugs were not permitted. Study candidates who could safely and under medical supervision come off their antidepressant were required to be off for at least 6 weeks before study participation. Triptans (e.g., sumatriptan, rizatriptan) were permitted-but no more than twice weekly and not within five elimination half-lives of that triptan before each test day or within five elimination half-lives of psilocin (15 h), the active metabolite of psilocybin, after experimental drug administration. A negative urine drug screen was required to qualify for the study and prior to each experimental drug administration. Use of psilocybin or other psychedelics for any purpose in the prior 3 months was not permitted. Caffeine and nicotine were not restricted in this study. Women of childbearing potential were required to use adequate birth control and have negative pregnancy testing for study qualification and prior to each experimental drug administration. Signed release of information was obtained to contact each participant's clinicians(s) in order to corroborate their migraine diagnosis and verify medical, psychiatric, and medication histories and general suitability for study participation. Research assistants and the principal investigator evaluated eligibility, obtained informed consent, and enrolled participants. In compliance with the Helsinki Declaration of 1975, as revised in 2000,written informed consent was obtained from every participant who took part in the study. Participants were quizzed on study procedures to ensure they were fully informed, and they were assured they could decline to participate in the study and were free to withdraw from the study at any time without penalty.
This clinical trial used a randomized, double-blind, placebocontrolled, parallel group design. The dose of psilocybin (psi) used was 10 mg, which approximates the weight-based dose in the original pilot study (10 mg/70 kg) and the amount used by patients with cluster headache who self-medicate with psilocybin-containing mushrooms.The placebo for this study was diphenhydramine (25 mg; diph), an antihistamine drug that produces mild acute sensory and perceptual changes as well as somnolence. Fatigue was frequently reported, and falling asleep was often observed after psilocybin administration in prior headache studies; therefore, diphenhydramine was anticipated to improve blinding integrity over the inert placebo used previously (MCC).Study participants completed two dosing sessions, 7 (±2) days apart, assigned to three randomization sequences: diph-diph (zero doses of psilocybin), diph-psi (one dose of psilocybin), and psi-psi (two doses of psilocybin) (Figure). A total of six participants were sought for each of the three groups. No statistical power calculation was conducted; instead, the sample size was based on the authors' previous experience with investigating psilocybin in headache disorders, including large effect sizes and realistic recruitment goals for a single-site study. The VACHS Investigational Drug Service generated the randomization assignment (i.e., both drugs in the pulse) for each participant at the time of receiving confirmation of their scheduled test dates. Drug
During screening and after enrollment, participants were informed about the procedures that take place during drug administration and the possible physiological and neuropsychological changes that occur with psilocybin and diphenhydramine. Participants were also provided details on methods of mitigating unpleasant experiences,
As in the pilot study, 2 change in migraine days/week over 2 weeks was of primary interest. Given the exploratory nature of this study, changes over the entire 8-week period after pulse completion were considered. Secondary outcomes included changes in migraine attacks/week, attack duration (hours), attack pain intensity (0 to 3 NRS), and associated symptom intensity (0 to 3 NRS); acute changes in vital signs; general drug effects (0 to 4 NRS); psychedelic ratings (5D-ASC); drug confidence (i.e., blinding) ratings (0 to 6 NRS); and incidence of adverse events (AEs).
Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and GraphPad Prism 10.4 (GraphPad Software, La Jolla, CA). All statistical tests were two-sided with an overall prehypothesis alpha threshold of 0.05. Descriptive statistics included means with standard deviation (SD) or 95% CIs for symmetrically distributed continuous data and counts with percentages for categorical variables. Due to the small sample size and deviation from the assumptions of parametric tests, all analyses used analogous nonparametric alternatives. Changes in diary measures from baseline over specific time periods were compared among groups using the Kruskal-Wallis test followed by pair-wise group comparisons using the Mann-Whitney U test. Changes in diary measures over time were compared using the nonparametric approach for repeated measures data,where the data were first ranked, and then fitted using a mixed effects model with an unstructured variance-covariance matrix and p-values adjusted for analysis of variance-type statistics (ATS). The model included group as a between-subjects factor, time as a within-subjects factor, and their interaction. The mixed effects approach is advantageous in that it is unaffected by randomly missing data and allows greater flexibility in modeling the correlation structure of F I G U R E 1 Randomization and study schedule. Participants were randomized to receive either zero, one, or two doses of psilocybin (10 mg; psi) between two dosing sessions 1 week apart. Diphenhydramine (25 mg; diph) was used as placebo. The headache diary was maintained starting 2 weeks before the first dosing session until 8 weeks after the second dosing session. | 5 HEADACHE repeated measures data.The 50% response rate was calculated as the proportion of participants who reached a reduction in migraine days/week of at least half and was compared among groups using Fisher exact test. Acute effects of drug administration on mean arterial pressure, heart rate, and general drug effects measured throughout the session were analyzed using the same nonparametric model for repeated measures with day included as an additional within-subjects factor. Psychedelic effects as measured on the 5D-ASC scale and calculated as a percent of the maximum possible score (total and each of the five dimensions) and drug confidence (i.e., blinding) were compared as above with test day as the only within-subjects factor. Potential associations between migraine frequency reductions and subjective ratings or confidence ratings were assessed using correlation (Spearman) analysis. The numbers of AEs were described as incidences; comparisons between drugs were carried out via Fisher exact test.
A total of 220 patients were prescreened for study participation between September 2021 and August 2023; 25 were enrolled in the study, but seven of these did not take part for various reasons (Figure). Two participants withdrew from the study after their first dosing session, one for the emergence of the SARS-CoV-2 Omicron variant that precluded travel and another for anxiety during the first session. The latter of these had an insufficient diary, as did one other study participant, leaving 16 in the final analysis, six receiving zero (diph-diph) doses of psilocybin, five receiving one (diph-psi) dose, and five receiving two (psi-psi) doses (Figure).
This study included two (12.5%) males and 14 (87.5%) females. The
Migraine frequency: Both diph-psi and psi-psi groups had reductions of approximately two migraine days/week (~60% reduction) sustained over 8 weeks (Table). Whereas the diph-diph group's reduction was numerically lower (reaching max ~40% reduction over 8 weeks), these differences did not reach statistical significance over 2, 4, or 8 weeks of the diary period, despite large effect sizes (Table). Looking week by week over the entire 8-week period (FigureThe 50% response rate over 2, 4, and 8 weeks was 17%, 33%, and 33%, respectively, in the diph-diph group (n = 6); 80%, 80%, and 80%, respectively, in the diph-psi group (n = 5); and 80%, 60%, and 80%, respectively, in the psi-psi group (n = 5; Figure). F I G U R E 2 Participant numbers. The enrollment and inclusion of participants in the final analysis are detailed.
There were no significant differences among groups over any time period. Other attack features: A significant group effect for attack duration was found over 2 [Χ 2 (2) = 8.46, p = 0.015] and 4 [Χ 2 (2) = 9.70, p = 0.008] weeks. Although reduced attack duration in the diphpsi group was seen, a baseline nearly double that recorded in either the diph-diph or psi-psi groups is noted (Table). There were no significant differences among groups over 2, 4, or 8 weeks in attack frequency (Table) or pain intensity (Table). No differences were seen in abortive medication use or other associated migraine symptoms, except for photophobia intensity over 8 weeks [Χ 2 (2) = 7.39, p = 0.025] with reduction seen in the diphdiph group (Table).
There were no group × time × day interactions with respect to vital signs. An effect of group × time × day was not observed for "overall" drug effects [num df = 7.07, ATS = 0.98, p = 0.444] but was observed for "nausea" ratings [num df = 9.60, ATS = 3.55, p < 0.001] reported during drug administration. The group × day interaction effects were significant for the percent maximum 5D-ASC scale score [num df = 1.99, ATS = 3.04, p = 0.048], as well as "oceanic boundlessness" [num df = 1.99, ATS = 4.51, p = 0.011], "visionary restructuralization" [num df = 1.99, ATS = 3.98, p = 0.019], and "auditory alteration" [num df = 2.00, ATS = 7.97, p < 0.001] dimension scores (Table). There were no significant correlations between migraine frequency change and total 5D-ASC scale score (r s = -0.365, p = 0.299), "overall" drug effects rating (r s = -0.284, p = 0.420), or other subjective or vital sign measures after psilocybin administration (remaining data not shown).
There was a significant group × day interaction for drug confidence ratings for psilocybin (num df = 2, ATS = 3.67, p = 0.025) but not for diphenhydramine (num df = 2, ATS = 1.22, p = 0.296) (Table). Significant changes in psilocybin confidence ratings from day 1 to day 2 were observed among those in the diph-psi group (2.2 to 5.6; p < 0.001) but not diph-diph (1.4 to 2.0; p = 0.611) or psi-psi (3.4 to 4.0; p = 0.593) groups. There was no correlation between confidence in having received either psilocybin (r s = -0.172, p = 0.534) or the actual drug received (r s = 0.115, p = 0.680; on day 2) and change in migraine frequency over 2 weeks or over any time period (4-and 8-week data not shown).
There were no serious or unexpected AEs in this study (Table). The most frequently reported AEs during dosing sessions were fatigue and nausea; only nausea was significantly different between drugs (more common with psilocybin, p = 0.002). The most frequently reported AEs in the 24 h after drug administration were fatigue and migraine; only fatigue was significantly different (more common after psilocybin, p = 0.008). All AEs were self-limiting or, in the case of migraine/headache, resolved with typical abortive therapy. No lasting physical or neuropsychological changes were reported out to 6-month follow-up with participants.
The present study was designed to explore whether a pulsed-dose regimen of psilocybin provided greater therapeutic benefit as a transitional migraine treatment over single-dose administration, as is reported in cluster headache. No difference between single or pulsed dosing was found, and interestingly, a statistically similar response was found with placebo (diphenhydramine). Whereas the groups receiving psilocybin appeared to separate from the group that only received placebo in the first few weeks after pulse completion with large effect sizes, these must be interpreted with caution due to the small sample size, which can lead to unstable and potentially inflated estimates. That the primary outcome did not achieve statistical significance, even looking over several time periods in the 8-week diary, suggests that the observed effect sizes may not reflect true differences but rather variability inherent in a small sample. TA B L E 1 Participant demographics and migraine history.
The use of an active placebo agent in this study was an important step in this line of research, helping to consider non-drug effects (i.e., placebo effect and blinding integrity) in the observed clinical outcomes. Diphenhydramine (25 mg) had been selected for its ability to mimic some of the acute subjective effects of low-dose psilocybin, although it is not expected to produce lasting therapeutic benefit in migraine after one or two doses. Therefore, non-drug effects likely played a role in the observed response, the most likely one being the placebo response, which is well-recognized in interventional drug studies in migraineas well as psychedelic drug trials.The placebo response results in clinical improvements not attributable to the direct pharmacological actions of the investigational drug and is driven by positive expectations, the patientpractitioner relationship, and other factors. The hype surrounding psychedelic medicine stemming from various media outlets and pop culture trends may raise expectations for success with this drug class.Unlike psychedelic studies outside of headache disorders, this study did not involve additional procedures, such as psychotherapy, which can enhance the patient-practitioner relationship. This particular confound is discussed further below. The placebo response cannot be measured, if the control drug does not adequately blind participants from the active drug. Anecdotally, both participants and staff present during drug dosing found it more difficult to speculate whether psilocybin or diphenhydramine was administered compared to previous studies with the pharmacodynamically inert MCC placebo. The measure used to gauge blinding-drug confidence ratings-only differed in the diph-psi group, who received different drugs on days 1 and 2. This suggests that diphenhydramine may not completely substitute for the acute effects of psilocybin when individuals receive both drugs. Otherwise stated, when a participant is exposed to both placebo and active drug, they may have greater confidence in differentiating the two conditions. Theoretically, this would be less of a concern in parallel group studies in which participants in each arm are assigned to only one intervention. These results have important implications for study design in future trials because within-subject crossover designs risk unblinding. Of note, drug confidence ratings in participants with prior classic psychedelic exposure (n = 4; most recently 1 year prior) did not differ from those without prior exposure, and therefore the context and duration between exposures may also be relevant. The shortcomings of diphenhydramine as a precise mimicker of psilocybin's acute subjective effects are acknowledged. For instance, diphenhydramine 25 mg is not expected to produce the degree of synesthesia or altered consciousness that psilocybin, even at the low dose of 10 mg, can produce in some individuals. Other drugs that might better mimic these effects include tetrahydrocannabinol (THC; the psychoactive constituent of cannabis) or dextromethorphan, an N-methyld-aspartate receptor antagonist.Although these agents, such as diphenhydramine, are not expected to have transitional effects after only one to two doses, administration could limit the use of the urine drug screen to assess for substance use outside the study. The identification of adequate TA B L E 3 Drug confidence ratings (i.e., blinding integrity) reported at the end of each test day. As in the pilot migraine study (and pilot cluster headache study),there were no correlations between the change in migraine frequency and either general drug effects or acute psychedelic effects after psilocybin administration. This dissociation between acute subjective effects and clinical effects after psilocybin or LSD has long been demonstrated by the practice of patients with cluster headache who commonly use low-and sub-psychedelic doses and have also described relief with nonpsychedelic congeners.The conventional use of pulsed DHE, which is a nonpsychedelic 5-HT 2A receptor agonist, in both migraine and cluster headachefurther supports this. The relationship between acute psychedelic effects and lasting therapeutic measures remains hotly debated in the field of psychedelic medicine, with some but not all studies in psychiatric conditions suggesting correlations.Furthermore, the constellation of practices known as psychedelic-assisted psychotherapy (PAP), which includes moderate-to-high-dose drug, enriched settings, and psychotherapy, were not carried out in this or the authors' previous psilocybinheadache studies.The PAP model poses challenges to the identification of drug versus non-drug effects, a concern also raised by the FDA,although certain individuals might benefit from this approach for their headache management. Going forward with larger scale clinical trials in migraine or other headache disorders, several factors will demand careful consideration in the study design, including the disease being studied, the expectations and needs of the individual being treated, the dose and frequency of drug administration, the integrity of blinding, the way psychedelic effects are measured, and the presence of other concomitant procedures and therapies. The present study has both strengths and limitations. The randomized, double-blind, placebo-controlled, parallel group design offers the most objective interpretation of findings of an otherwise exploratory study. The use of diphenhydramine as the placebo agent allowed for a measure of placebo response, although it did not fully substitute for the acute subjective effects of low-dose psilocybin. Either a higher dose of diphenhydramine or another acutely psychoactive agent, such as THC, could be explored. Although a measure of blinding integrity for study participants was used, a measure of research staff blinding was not obtained but should be included in future studies. A formal measure of participant expectation taken prior to starting study procedures was also not obtained but should be included in future studies to capture this important factor in the placebo response.As in previously published psilocybin-headache studies, the number of participants in the present study is small, limiting the power of statistical analyses and the generalizability of the findings. This study also included participants with either episodic or chronic migraine, subtypes of the disease typically studied separately as distinct entities.
Whereas this exploratory study failed to show a statistically significant difference in migraine reduction between a single-dose and a two-dose pulse of psilocybin, further research is necessary to consider whether pulsed dosing of the drug (as in done in cluster headache) may offer additional benefits in either amplitude or duration of effects over a single dose. The reduction in migraine frequency seen in the placebo group, where only diphenhydramine was received, suggests that non-drug effects-most likely placebo effects-drove some of the therapeutic effects seen in this study. Further rigorous scientific investigation of psilocybin in migraine is warranted. These studies should include suitable active placebos, measures of expectation and blinding integrity, and be carefully tailored to migraine disease and its particular treatment standards.