The Potential of Psychedelics for the Treatment of Episodic Migraine

This article is a narrative review of the literature on psychedelics in headache disorders, supplemented by previously unpublished secondary analyses drawn from a double-blind, crossover clinical study of psilocybin in people with migraine. The review integrates historical reports, case series (including cluster headache self-treatment), pharmacological considerations and findings from the controlled study. The controlled study enrolled people meeting ICHD-3 beta criteria for migraine with at least two attacks per week, thereby including both episodic and chronic migraine at the specified burden. Key exclusion criteria reported were serious medical illness, current manic or psychotic disorders, recent antidepressant use (off for at least six weeks), and positive drug/alcohol tests. Triptans were permitted with restrictions (no more than twice weekly and not within five half-lives of dosing). All participants received placebo (microcrystalline cellulose) on the first dosing day and psilocybin (10 mg/70 kg) two weeks later under enhanced blinding so staff and participants were unaware of dose order. During dosing days, vital signs were monitored and subjects periodically rated drug effects; headache-related symptoms (pain intensity, photophobia, phonophobia, nausea, functional impairment) were recorded on a 0–3 numerical rating scale at baseline, at 30 and 60 minutes, then hourly up to 6 hours. Participants also completed headache diaries from two weeks before the first dosing day until two weeks after the second dosing day. Changes from baseline in the two weeks after dosing were compared between placebo and psilocybin using paired t-tests; weekly migraine days was treated as an outcome of interest, though primary outcomes were not prespecified for this exploratory analysis. The final analysis included ten subjects overall; the episodic migraine subgroup analysed in this review comprised five subjects.

Findings relevant to acute (abortive), preventive and transitional applications are presented separately. Regarding abortive effects, the controlled study produced only very limited evidence. Four participants had an acute migraine at the start of both placebo and psilocybin dosing days and only two of those were episodic migraine cases. In these two individuals one subject (31-year-old man) showed reductions in attack pain and light sensitivity during the psilocybin session that did not persist on the placebo day, and another (59-year-old woman) experienced faster symptom relief with psilocybin than with placebo. The authors emphasise that these observations from two subjects are insufficient to validate abortive efficacy. Preventive use (regular, chronic dosing) is not supported by the literature and is not recommended. The authors note an observational case series in persistent pain disorders where patients used low, frequent doses of psilocybin-containing mushrooms, but they caution against extrapolating those reports to episodic migraine. Safety concerns are highlighted by historical experience with methysergide, a preventive agent related to LSD that caused tissue fibrosis mediated by 5-HT2B receptor activity. Reported affinities for 5-HT2B vary across psychedelics (for example LSD and psilocin show relatively high affinity in some assays, whereas DMT shows lower affinity), and the consequences of long-term, frequent exposure to compounds interacting with 5-HT2B and other systems are unknown. Transitional effects constitute the most promising signal. In the secondary analysis of the episodic subgroup (n = 5: three women, two men; all Caucasian; mean age 39.8 years, mean age at migraine onset 21.2 years, mean BMI 23.3 kg/m2), psilocybin produced significant reductions in weekly migraine days compared with placebo. The report states a statistically significant between-condition difference in reduction of weekly migraine days (p = 0.003, effect size d' = 1.37) and describes the reduction in weekly migraine days as approximately 50%, similar to findings in the main study. Significant between-condition reductions were also observed for weekly migraine attacks and pain intensity. Improvements after psilocybin were recorded for attack duration, photophobia, phonophobia, nausea and functional impairment but these did not reach statistical significance versus placebo. Acute subjective psychedelic intensity, measured by the 5-Dimensional Altered States of Consciousness (5D-ASC) scale, did not correlate with percent reduction in migraine days (r = 0.300, p = 0.680). No serious or unexpected adverse events were reported in the study. The authors note that the controlled study examined only a single psilocybin administration at 10 mg/70 kg with a two‑week follow-up, and that an ongoing trial will evaluate repeating psilocybin after one week (NCT04218539).

Schindler frames the available evidence as supportive of further investigation of psychedelics—particularly psilocybin—for transitional treatment in episodic migraine, while advising against focusing on abortive or preventive applications at this time. Transitional use is emphasised because psychedelics can produce sustained improvements after a brief exposure without the need for continuous drug presence, distinguishing them from conventional daily preventives. The authors argue that migraine-specific study designs are required rather than models imported from psychiatric psychedelic-assisted psychotherapy, noting that acute subjective psychedelic intensity does not appear to explain therapeutic benefit in migraine or cluster headache in the reported data. Key limitations acknowledged include the preliminary and small-scale nature of the controlled data: the main study had only ten subjects in the final analysis and the episodic subgroup comprised five participants, follow-up was short (two weeks post-dosing), and only a single dose and regimen were evaluated. Safety uncertainties relevant to longer-term or frequent dosing are also emphasised, drawing attention to historical adverse events with methysergide and to variable receptor affinities among psychedelics. The authors recommend larger, better-powered studies with representative samples, dose–response characterisation, investigations of repeat or pulsed regimens, longer follow-up, and exploration of combination approaches with conventional migraine treatments. They caution that the current enthusiasm surrounding psychedelics in mental health should not dictate protocols for headache research and that research priorities should be tailored to the clinical realities of migraine.

Several converging lines of evidence suggest therapeutic potential for classic psychedelics in headache disorders. The only controlled data in episodic migraine are reported here and indicate preliminary abortive and transitional effects of psilocybin, with the transitional signal being the most compelling. The authors advise against prioritising abortive use because of practical limitations of inducing acute psychedelic states to treat attacks, and they caution strongly against preventive strategies involving chronic or near-daily dosing because of unknown long-term risks and historical examples of harm. Overall, Schindler concludes that transitional application of psychedelics warrants further research in episodic migraine, and that future studies should be designed specifically for headache medicine rather than modelled on psychiatric protocols.