Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Efficacy and safety of galcanezumab as chronic cluster headache preventive treatment under real world conditions: Observational prospective study.

BACKGROUND: Calcitonin gene-related peptide has shown to play a central role in cluster headache (CH) pathophysiology. A clinical trial with galcanezumab was carried out in chronic cluster headache (CCH) but did not meet its primay endpoint. However, its off-label use in patients with CCH refractory to other therapies could be considered. We aimed to asses the efficacy and safety of galcanezumab as CCH preventive treatment in a real-life setting. METHODS: An observational study was conducted. Patients with CCH who received at least one dose of 240 mg of galcanezumab. RESULTS: Twenty-one patients who tried a mean of 6.3 ± 1.9 preventive therapies, including onabotulinumtoxinA in 90.5%. At baseline, the median of frequency was 60 (37.5-105) monthly attacks with 10 (8.3-10) points in pain intensity (Numerical Rating Scale). After one month, the frequency decreased to 31 (10.5-45) (p = 0.003) with 8.5 (8-9.5) intensity (p = 0.007); 10 (47.6%) patients were 50% responders of whom four (19%) were 75% responders. Of the 15 patients with 3 months of follow-up, seven (46.6%) reduced their frequency by 50% and four (26.6%) by 75%, with 40 (10-60) monthly attacks (p = 0.07) and pain intensity of 8 (5-10) (p = 0.026). Some 52% patients experienced adverse events, mostly mild. CONCLUSIONS: In our cohort of refractory CCH, galcanezumab was effective in almost 50% of patients. This finding supports individual off-label treatment attempts.

Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

One-year prevalence of cluster headache, hemicrania continua, paroxysmal hemicrania and SUNCT in Norway: a population-based nationwide registry study.

BACKGROUND: There is lack of population-based studies evaluating the prevalence of paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks. OBJECTIVES: The aim of this study was to investigate the gender-specific 1-year prevalence of cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks. METHODS: A nationwide study was conducted from January 1 2022 and December 31 2022 by linking diagnostic codes from Norwegian Patient Registry and prescription of relevant drugs from Norwegian Prescription Database on an individual basis. The 1-year prevalence with 95% confidence intervals (CI) of cluster headache, paroxysmal hemicrania, hemicrania continua and short-lasting unilateral neuralgiform headache attacks are estimated based on the combination of diagnostic codes, prescription of drugs and corresponding reimbursement codes. RESULTS: Among 4,316,747 individuals aged ≥ 18 years, the 1-year prevalence per 100,000 was 14.6 (95% CI 13.5-15.8) for cluster headache, 2.2 (95% CI 1.8-2.7) for hemicrania continua, 1.4 (95% CI 1.0-1.8) for paroxysmal hemicrania, and 1.2 (95% CI 0.8-1.4) for short-lasting unilateral neuralgiform headache attacks. For all the trigeminal autonomic cephalalgies, cluster headache included, the prevalence was higher for women than men. CONCLUSIONS: In this nationwide register-based study, we found a 1-year prevalence per 100,100 of 14.6 for cluster headache, 2.2 for hemicranias continua, 1.4 for paroxysmal hemicranias, and 1.2 for short-lasting unilateral neuralgiform headache attacks. This is the first study reporting higher prevalence of cluster headache for women than men.

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity.

OBJECTIVE: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). BACKGROUND: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. METHODS: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. RESULTS: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = -0.81), implicating this neural pathway in treatment response. CONCLUSION: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial.

ABSTRACT: Activation of adenosine triphosphate-sensitive potassium (K ATP ) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a K ATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo ( P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo ( P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo ( P = 0.037). These findings demonstrate that K ATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of K ATP channel inhibitors as therapeutic agents for cluster headaches.

Preventive therapy with galcanezumab for two consecutive cluster bouts in patients with episodic cluster headache: an observational multicenter study.

BACKGROUND: Cluster headache is a severe and disabling primary headache disorder. Galcanezumab is a monoclonal antibody against calcitonin gene-related peptide and a preventive therapy for episodic cluster headache. However, the approval and insurance coverage for episodic cluster headache differ in each country. Additionally, the consistency of efficacy of galcanezumab therapy has not yet been evaluated. This study aimed to assess the efficacy and safety of 240 mg of galcanezumab therapy for consecutive cluster bouts in patients with episodic cluster headache. METHODS: The study enrolled patients with episodic cluster headache who received two courses of galcanezumab therapy at three university hospitals in Republic of Korea between February 2020 and April 2022. The efficacy and safety of galcanezumab were analyzed by comparing daily headache frequency, the number of headache days, and headache intensity and adverse effects during the one-week period before and the third week after galcanezumab injection for each episode of cluster bouts. Paired t-test was used for comparing repeated data from different episodes of cluster bout. RESULTS: Sixteen patients were enrolled in this study. Fourteen patients received galcanezumab therapy for two consecutive cluster bouts. Galcanezumab was administered 24 days and 11 days after the first and second cluster bouts, respectively. The proportion of patients with 50% or more reduction in frequency of daily headache at week 3 from baseline was 86% and 64% during the first and second episodes, respectively. The proportion of patients who received transitional therapy before galcanezumab therapy was higher in the first episode of cluster bout than that in the second episode of cluster bout. No serious adverse reactions or significant differences in adverse effects between cluster bouts were noticed. Two patients received a second galcanezumab therapy during the pre-cluster period, and their cluster periods ended without typical cluster headache attacks 10-60 days after galcanezumab therapy. CONCLUSIONS: This exploratory analysis suggests that galcanezumab may be effective as a preventive therapy in subsequent cluster bouts. Patients with episodic cluster headaches who underwent galcanezumab therapy tended to receive a second round of treatment in the early stages of their next cluster bout without transitional therapy.

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

SYMPATHETIC NERVE ENTRAPMENT POINT INJECTION AS AN ADJUVANT TREATMENT FOR INTRACTABLE CLUSTER HEADACHE: A CASE REPORT.

BACKGROUND: Cluster headache (CH) is characterized by severe unilateral pain ranging from the orbital to the temporal regions with ipsilateral autonomic manifestations. Although most patients respond to drugs or oxygen inhalation, some do not. In this case report, we introduce sympathetic nerve entrapment point injection (SNEPI), a new adjuvant treatment for CH. CASE REPORT: We introduce two CH patients who did not respond well to pharmacological treatment or 100% oxygen inhalation, but who improved after SNEPI. Patient 1, a 42-year-old man, visited the Emergency Department (ED) with severe periorbital right frontal headache accompanied by ipsilateral rhinorrhea, conjunctival injection, and eyelid edema. The symptoms did not fully respond to drugs or oxygen inhalation, but improved after SNEPI into the tender point of the splenius capitis (SC) muscle; there was no further pain for 1 month thereafter. Patient 2, a 26-year-old woman, presented to the ED complaining of severe headache in the right supraorbital-temporal-occipital region with ipsilateral lacrimation and conjunctival congestion. The patient was taking various drugs for CH, but there was no improvement; the symptoms improved dramatically after SNEPI into the tender points of the SC and paraspinal deep muscles (levels T1-2), and the pain was well managed with reduced drug doses for 3 months. Why Should an Emergency Physician Be Aware of This? CH can cause severe acute pain, and sometimes pharmacological treatment or oxygen inhalation is not effective. SNEPI, which is inexpensive and can be easily performed, may be considered as an adjuvant treatment for intractable CH in the ED.

Transient side shift of cluster headache attacks after unilateral greater occipital nerve injection.

Attacks of cluster headache (CH) are usually side-locked in most, but not all, patients. In a few patients, the side may alternate between or, rarely, within cluster episodes. We observed seven cases in whom the side of CH attacks temporarily shifted immediately or shortly after unilateral injection of the greater occipital nerve (GON) with corticosteroids. In five patients with previously side-locked CH attacks and in two patients with previously side-alternating CH attacks, a side shift for several weeks occurred immediately (N = 6) or shortly (N = 1) after GON injection. We concluded that unilateral GON injections might cause a transient side shift of CH attacks through inhibition of the ipsilateral hypothalamic attack generator causing relative overactivity of the contralateral side. The potential benefit of bilateral GON injection in patients who experienced a side shift after unilateral injection should be formally investigated.

Treatment pattern and response for cluster headache in Korea: A prospective multicenter observation study.

BACKGROUND: Only limited data are available regarding the treatment status and response to cluster headache in an Asian population. Therefore, this study aimed to provide a real-world treatment pattern of cluster headache and the response rate of each treatment in an Asian population. METHODS: Patients with cluster headache were recruited between September 2016 and January 2019 from 16 hospitals in Korea. At the baseline visit, we surveyed the patients about their previous experience of cluster headache treatment, and acute and/or preventive treatments were prescribed at the physician's discretion. Treatment response was prospectively evaluated using a structured case-report form at 2 ± 2 weeks after baseline visit and reassessed after three months. RESULTS: Among 295 recruited patients, 262 experiencing active bouts were included. Only one-third of patients reported a previous experience of evidence-based treatment. At the baseline visit, oral triptans (73.4%), verapamil (68.3%), and systemic steroids (55.6%) were the three most common treatments prescribed by the investigators. Most treatments were given as combination. For acute treatment, oral triptans and oxygen were effective in 90.1% and 86.8% of the patients, respectively; for preventive treatment, evidence-based treatments, i.e. monotherapy or different combinations of verapamil, lithium, systemic steroids, and suboccipital steroid injection, helped 75.0% to 91.8% of patients. CONCLUSION: Our data provide the first prospective analysis of treatment responses in an Asian population with cluster headache. The patients responded well to treatment despite the limited availability of treatment options, and this might be attributed at least in part by combination of medications. Most patients were previously undertreated, suggesting a need to raise awareness of cluster headache among primary physicians.

Medication adherence in patients with cluster headache and migraine: an online survey.

To examine factors for adherent and non-adherent behavior in patients with cluster headache and migraine. Adults with cluster headache or migraine were included in this anonymous online survey using a questionnaire accessed via homepages of headache support groups. Medication adherence in preventive treatment was measured with the Medication Adherence Report Scale (MARS-D). Factors for non-adherent behavior were examined (subjective socioeconomic status, psychological comorbidities, self-efficacy, coping, side effects, expectations of treatment, information on medical treatment, and trust in the physician/treatment concept). 200 participants (n = 58 with cluster headache, n = 142 with migraine) were included. The rate of medication adherence in preventive treatment was 32.8% for participants with cluster headache and 20.4% for migraine. The most common reasons for low adherence in participants with cluster headache were altering the prescribed medication dose (34%) or taking less than instructed (14%), which was mostly due to insufficient benefit from the medication or side effects. Positive expectations of medical treatment (p ≤ 0.05) correlated significantly with adherent behavior in cluster headache. Furthermore, the adherence-promoting factors coping and self-efficacy were more pronounced in patients with cluster headache than in those with migraine (p < 0.05). This study is the first to comprehensively investigate medication adherence and factors influencing adherent/non-adherent behavior in patients with cluster headache. Patients with cluster headache had similar adherence levels to patients with migraine, but had higher resources of adherence-promoting factors.

Effectiveness and safety profile of greater occipital nerve blockade in cluster headache: a systematic review.

BACKGROUND: Greater occipital nerve (GON) blockade is a short-term preventive therapy for cluster headache (CH). We conducted a systematic review to evaluate the effectiveness and safety of GON blockade in patients with CH. METHODS: On 23 October 2020, we searched MEDLINE, Embase, Embase Classic, PsycINFO, CINAHL, CENTRAL and Web of Science databases from their inception date. Studies included participants with a CH diagnosis who received corticosteroid and local anaesthetic suboccipital region injections. Outcomes were change in the frequency/severity/duration of attacks; proportion of participants responding to treatment, time to attack freedom from an attack, change in attack bout length and/or the presence of adverse effects after GON blockade. Risk of bias was assessed with the Cochrane Risk of Bias V.2.0 (RoB2)/Risk of Bias in Non-randomized Studies - of Interventions (ROBINS- I) tools and a specific tool for case reports/series. RESULTS: Two RCTs, eight prospective and eight retrospective studies, and four case reports were included in the narrative synthesis. Every effectiveness study found a significant response in one or more of frequency/severity/duration of individual attacks or proportion of patients responding to treatment (47.8%-100.0%). There were five instances of potentially irreversible adverse effects. A higher injectate volume and use of concurrent prophylaxis may be associated with an increased likelihood of response. Methylprednisolone may have the best safety profile of available corticosteroids. DISCUSSION: GON blockade is safe and effective for CH prevention. Higher injectate volumes may improve likelihood of response, and the likelihood of serious adverse events may be reduced by using methylprednisolone. PROSPERO REGISTRATION NUMBER: CRD42020208435.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

[Galcanezumab for episodic and chronic cluster headache]. / Galcanezumab bei episodischem und chronischem Clusterkopfschmerz.

BACKGROUND: Cluster headache (CH) is a highly debilitating headache disorder characterized by frequent attacks of excruciating unilateral pain accompanied by cranial autonomic symptoms. Calcitonin gene-related peptide (CGRP) is implicated in the pathophysiology of CH. OBJECTIVES: Preventive efficacy and tolerability of the anti-CGRP antibody galcanezumab in patients with episodic (eCH) and chronic CH (cCH). Review of the study results and the challenges in developing drugs for the preventive treatment of CH. MATERIALS AND METHODS: In two international multicenter phase III trials galcanezumab 300 mg given subcutaneously every 4 weeks was compared with placebo. The double-blind study period (8 weeks in eCH, 12 weeks in cCK) was preceded by a baseline period in both trials. The primary endpoint was the reduction in weekly attack frequency. RESULTS: In the eCH trial, 106 patients were randomized to either galcanezumab (n = 49) or placebo (n = 57). The mean weekly attack frequency during the first 3 weeks decreased by 52% in the galcanezumab group compared with 27% in the placebo group (p = 0.036). In the cCH trial, 237 patients were randomized to galcanezumab (n = 117) or placebo (n = 120). The primary endpoint was not met in this study. The reduction in mean weekly attack rate was 5.4 with galcanezumab versus 4.6 with placebo (p = 0.334). Galcanezumab was well tolerated in both studies. CONCLUSIONS: Galcanezumab had a significant effect in the prevention of eCH attacks but not in cCH. Possible reasons for this discrepancy are discussed.

Intermediate cervical plexus block in the management of treatment resistant chronic cluster headache following whiplash trauma in three patients: a case series.

OBJECTIVES: Cluster headaches are an intensely painful and debilitating headache disorder. Conventional management includes abortive and preventative agents. A fifth of patients with chronic cluster headaches can be refractory to conventional treatment. Cluster headache can develop following whiplash trauma to the head and neck. CASE PRESENTATION: Three patients were referred to a tertiary pain medicine unit in a university teaching hospital with treatment-resistant chronic cluster headache. They were treated with a novel intervention namely, ultrasound-guided intermediate cervical plexus block with depot methylprednisolone. Patient one reported chronic cluster headache for three years. Patient two reported episodic cluster headache that appeared to be evolving into chronic cluster headache. Patient three reported bilateral cluster headache following a motor vehicle accident. Intermediate cervical plexus block provided significant and durable relief in three patients with treatment resistant chronic cluster headache. CONCLUSIONS: The novel intervention may have played a role in aborting and preventing chronic cluster headaches.

Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: Case series and narrative review.

BACKGROUND: Galcanezumab, a monoclonal antibody targeting calcitonin gene-related peptide (CGRP), has demonstrated clinical benefit as a preventive treatment of episodic cluster headache (ECH) but not in chronic cluster headache (CCH) to this date. Our objective was to analyze our clinical experience of the compassionate use of galcanezumab in cluster headache and to conduct a narrative review of the published literature. METHODS: We present a case series of patients with refractory ECH and CCH treated with 240 mg galcanezumab monthly in an outpatient headache clinic. We recorded epidemiologic and clinical data and analyzed the disease evolution after 3 and 6 months. The review was performed following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: We included three patients with ECH who were treated during a refractory cluster bout (mean duration of 83.7 days since the first attack, range 46.0-105.0 days) and six patients with CCH who had a high frequency of attacks (mean 35.8 attacks/week, range 7-56) and refractory to a mean of 5.2 preventive treatments (range, 3-9). In the CCH group, >50% frequency reduction was seen in 83% (5/6 patients) and the number of attacks per week showed a mean reduction of -24.2 at month 3 (range, -6 to -49) and -27.6 at month 6 (range, -7 to -49). In the ECH group, the bout ended a mean 17.3 days (range, 10-28) after galcanezumab administration. One third of patients reported mild adverse events, none of them leading to discontinuation. CONCLUSION: In conclusion, our clinical experience supports the use of galcanezumab in patients with refractory cluster headache. These results might encourage the possibility of continuing clinical development with randomized controlled trials of anti-CGRP treatments in patients with cluster headache.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. BACKGROUND: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. METHODS: Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. RESULTS: In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] -2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and -3.2 (95% CI -8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. CONCLUSIONS: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.