Low-dose psilocybin in short-lasting unilateral neuralgiform headache attacks: results from an open-label phase Ib ascending dose study

Short-lasting unilateral neuralgiform headache attacks (SUNHA) are classified as trigeminal autonomic cephalalgias and consist of very short, intense unilateral head pains accompanied by ipsilateral cranial autonomic features such as lacrimation, conjunctival injection and nasal symptoms. The pathophysiology remains incompletely understood but may involve hypothalamic dysfunction and trigeminal neurovascular conflict; cognitive and affective factors are also thought to influence symptom persistence and disability. There are no treatments approved specifically for SUNHA; management relies on off-label neuropathic agents and a range of interventional procedures, yet a substantial proportion of patients remain refractory to available therapies. Rucker and colleagues designed an open-label Phase Ib ascending dose study to explore low-dose oral psilocybin, administered with psychological support, in people with chronic SUNHA. The stated objectives were to assess safety and tolerability, to characterise acute effects on cognition (the pre-specified primary aim), and to measure effects on headache severity and frequency using daily diaries and standard outcome instruments. The study was motivated by preliminary signals that psychedelics may affect related headache disorders and by the need for alternative approaches in this rare but disabling condition.

Rucker and colleagues ran a pre-registered (clinicaltrials.gov NCT04905121) open-label Phase Ib ascending dose study. Eligible participants entered an active treatment phase with three dosing visits; the intended dosing schedule was oral synthetic psilocybin (GMP-manufactured) given in capsules at 5 mg on Day 1 (±2 days), 7.5 mg on Day 6 (±2 days), and 10 mg on Day 11 (±2 days). Participants remained in clinic until medically cleared for discharge and received a telephone follow-up the day after dosing to assess need for psychological support. The psychological support model followed the common contemporary three-phase approach (preparation, dosing support, integration). The pre-specified primary outcome was cognition during the acute psychedelic experience, measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB) on three occasions per dosing visit: 60–45 minutes pre-dose, 90–100 minutes post-dose, and 360 minutes post-dose. Subjective acute effects were assessed after the dosing session with the five-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). Headache outcomes comprised daily headache diaries (frequency, duration, intensity) collected from screening through final follow-up and the six-item Headache Impact Test (HIT-6) administered prior to each dosing session and at Day 16 follow-up. Global clinical impressions were rated by participants and clinicians using the Clinical Global Impression (CGI) scale. Adverse events and vital signs were monitored throughout. Statistical analyses used SAS v9.4. Continuous results are presented as mean (standard deviation) unless stated otherwise. Paired t-tests compared performance on 11 CANTAB subdomains before versus after each dose, with a significance threshold of p < 0.05. As the trial progressed and recruitment proved limited, the investigators performed a post hoc qualitative analysis: an inductive thematic analysis of 22 applicable free-text clinical notes from dosing and follow-up visits to identify emergent themes in participant experience.

Recruitment ran from August 2021 to April 2022. Of 19 referrals, 15 failed pre-screening (mostly due to concomitant medications or comorbid disorders) and one was excluded before enrolment because safe medication tapering could not be supported. Four participants were enrolled; three completed all three planned doses and one withdrew after the first dosing session because of worsening pain. Subjective acute effects were more intense than anticipated. Only a single participant was able to complete the CANTAB battery at the 90-minute timepoint for the 5 mg and 7.5 mg sessions, and no participants could complete it at the 10 mg session owing to altered states of consciousness. Across the three doses there were no statistically significant differences on any CANTAB subdomain scores before versus after dosing, but primary outcome data could not be meaningfully analysed because of incomplete testing during the acute period. Mean 5D-ASC scores (subjective altered-state intensity) were higher than predicted from prior literature (reported mean ranges in the extracted text were 37.8–45.7), and scores did not show a simple linear dose–response in all participants. No serious adverse events occurred and no clinically significant abnormalities in vital signs were recorded during dosing. One participant reported vivid dreams after a 5 mg dose. Headache impact as measured by HIT-6 remained in the severe range throughout the trial (mean HIT-6 scores reported around 64.3–65.7) with no meaningful group-level change. Diary data at final follow-up showed heterogeneous clinical courses: two participants experienced reductions in mean daily attack frequency of >50% (from 22.9 to 11.0 and from 56.4 to 28.0), one participant had no change, and one participant worsened during the trial but returned to baseline frequency at final follow-up. In the two participants with reduced frequency there were also reductions in average headache duration and mean severity. On the CGI scale at final follow-up, two completers and their clinicians recorded "much" improvement and one recorded "minimal" improvement. The post hoc thematic analysis of clinical notes identified a prominent "psychological insights" theme, with participants reporting altered relationships to their headache pain and changes in illness conceptualisation and acceptance. The qualitative analysis was limited by the small number of participants and the retrospective use of clinical notes rather than prospectively collected qualitative data.

The investigators stress that the small sample size and open-label design preclude any conclusions about efficacy. Recruitment challenges — attributed to the rarity of SUNHA, stringent exclusion criteria related to comorbid affective disorders, and concomitant medication use — forced early termination of the trial before planned enrolment targets were met. The unexpectedly intense subjective effects of even modest psilocybin doses prevented the collection of the planned acute cognitive data and led to higher-than-anticipated 5D-ASC scores, undermining the primary outcome assessment. Rucker and colleagues note that expectancy effects likely contributed to participants' experiences and responses, citing a nonlinear relationship between dose and subjective altered-state scores in some cases and the broader literature on set and setting. While acknowledging that expectancy and contextual factors may exaggerate observable effects in psychedelic trials, the authors caution against dismissing such effects outright and suggest they may form part of the therapeutic phenomenon. The thematic analysis led the investigators to highlight psychological insights and shifts in illness perception as important aspects of the participant experience; these shifts occurred despite limited objective change in headache measures for most participants. The authors link this observation to literature on cognitive and behavioural factors in headache disorders and propose that increases in self-compassion, acceptance and reduced catastrophising could plausibly mediate subjective improvements. Limitations are emphasised: the small sample, lack of a placebo control, open-label protocol, early termination, and the HIT-6's potential insensitivity to short-term change. The qualitative work was conducted post hoc by members of the study team on routine clinical notes rather than on data collected for a predefined qualitative study. For future work the authors suggest exploring non-hallucinogenic psychedelic analogs and designs that better account for expectancy and contextual influences, while continuing to consider both neurological mechanisms and psychological aspects of living with chronic SUNHA.

This Phase Ib open-label study did not reach planned recruitment targets and was unable to produce definitive data on the pre-specified cognitive primary outcome because participants reported unexpectedly intense subjective effects that limited acute testing. Two of the three completers experienced a >50% reduction in attack frequency, but the small, uncontrolled sample prevents efficacy claims. The investigators conclude that psychological factors and shifts in patients' relationship to their pain emerged as notable components of the intervention effect and warrant further investigation. They recommend future research that addresses recruitment barriers, considers non-hallucinogenic analogues, and integrates attention to both neurological mechanisms and psychological processes in SUNHA management.