Craigo

Non-Invasive Vagus Nerve Stimulation in Cluster Headache: A Clinical Practice Guideline Peter J. Goadsby, Alexander Feoktistov, Magdalena Anitescu, Miles Day, Peter Staats Published in Pain Practice on October 6, 2025 Link: https://doi.org/10.1111/papr.70084 Abstract: Cluster headache (CH) is a rare but severe primary headache disorder characterized by recurrent attacks of unilateral, typically periocular pain lasting 15 min to 3 h, accompanied by ipsilateral autonomic symptoms and restlessness or agitation. Attacks may occur multiple times daily and present in clusters lasting weeks to months, interspersed with remission periods in episodic CH, or without remission in chronic CH. This review summarizes the clinical evidence supporting the use of transcutaneous cervical vagus nerve stimulation (tcVNS) for both the acute and preventive treatment of CH. Relevant clinical trials, real-world studies, and guideline recommendations are discussed. Pharmacological therapy for CH includes triptans and high-flow oxygen for acute management, and verapamil, corticosteroids, or galcanezumab for prevention. For patients with inadequate response or intolerance to these options, neuromodulation may be required. TcVNS has emerged as a noninvasive, safe, and effective alternative to invasive neuromodulation. Clinical trials have demonstrated significant reductions in attack frequency and intensity, leading to U.S. Food and Drug Administration (FDA) clearance and UK National Institute for Health and Care Excellence (NICE) approval for both acute and preventive treatment of CH. TcVNS represents a well-tolerated, noninvasive neuromodulatory option for patients with cluster headache, offering both acute and preventive benefits. This paper provides an overview of the current evidence, mechanisms of action, and practical guidelines for incorporating tcVNS into clinical management.

I’d like to offer a contemporary perspective on recent patient reports from the cluster headache (CH) community alongside my own experience regarding the treatment of CH with nutritional interventions. This draws on a range of emerging research to explore how modulation of the gut microbiota more so than any one diet may present as a novel future therapeutic target in CH. As best I can as a CH patient, I will attempt to integrate the converging lines of evidence that support this hypothesis including a case report, drawn from the grey literature, illustrating the clinical application of such a targeted microbiome-based approach and conclude with some final thoughts on what really is a fascinating subject. More bacteria than we are human... The human genome encodes for between 20,000 and 25,000 genes. In remarkable comparison our collective microbial genome, comprised of trillions of microbes that inhabit our bodies, contains an estimated 3,000,000 to 4,000,000 million genes. The gut microbiota is a vast community of bacteria, fungi, viruses and archaea that inhabit the gastrointestinal tract, with the highest density of microbes anywhere in the body found in the colon. The diversity of this community is influenced by a number of factors including diet, environment, motility, autonomic tone, antibiotic exposure, previous infection, vitamin D3 and psychedelics (more on the vitamin D3 and psychedelics later). Their primary energy source is dietary fibre and other non-digestible carbohydrates of which they ferment into short-chain fatty acids (SCFA’s) such as acetate, propionate and butyrate. They also synthesize vitamins such as vitamin K and several B-group vitamins, amino acid derivatives like indole and GABA and secondary bile acids that in turn regulate metabolism and immune function. Together these microbes and their metabolites play an existential role in maintaining gut integrity, modulating inflammation and supporting our overall health. Balance is the key to life... that sentiment resonates with me... When this community of microbes is balanced, or in eubiosis, the relationship is mutually beneficial. We nourish the microbes and they nourish us. When the balance of this community is disrupted, disease may follow through a process referred to as dysbiosis. Imbalance of the microbiota may degrade the mucin layer, a protective layer of mucous that protects the epithelial lining of the gut. When the mucosal layer is degraded, disruption may occur at the level of the epithelium where the tight junctions that maintain integrity of permeable membranes are compromised, increasing the translocation of toxins from the gut into blood and lymph where they invoke an immune response. An example of this is lipopolysaccharide (LPS), a structural component of the outer membrane of gram-negative bacteria. LPS engages the toll like receptor 4 (TLR4) complex on innate immune cells, activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which translocates to the nucleus and upregulates the expression of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). This cascade contributes to a process commonly referred to as “leaky gut” syndrome. Emerging Migraine Research... Whilst CH and migraine are clinically distinct disorders they do share several overlapping mechanisms including activation of the trigeminovascular system and neurogenic inflammation, as well as responsiveness to medications such as triptans and anti-CGRP monoclonal antibodies such as Emgality. Both conditions also exhibit cyclical patterns and hypersensitivity within pain processing networks. Given the larger body of research on migraine, it is useful to cautiously draw insights from migraine studies given they may reveal potential pathophysiological processes and therapeutic targets relevant to CH. In my view recent literature seems to have shifted the understanding of migraine from a neurovascular disorder toward a systemic inflammatory condition modulated by the gut-brain-immune axis. Multiple independent studies now converge on the idea that gut dysbiosis and intestinal permeability are central to migraine pathophysiology. A study by He et al. (2023) confirmed a causal relationship between gut microbial composition and migraine risk, identifying protective taxa such as Bifidobacteriales and pathogenic associations with Anaerotruncus and Clostridium genera, providing what I believe was the first robust evidence that microbiota composition can directly influence migraine susceptibility. In a 2024 study, Vuralli et al. found elevated serum LPS, VE-cadherin, HMGB1 and IL-6 in chronic migraine patients with medication overuse, supporting a “leaky-gut” inflammatory phenotype linked to trigeminal sensitization. Recent reviews and meta-analyses converge on much the same theme; migraineurs show lower microbial diversity, depletion of SCFA producing species such as Faecalibacterium and Roseburia and a relative overgrowth of pro-inflammatory species. Emerging clinical research supports therapeutic modulation of the microbiota. Grodzka and Domitrz (2025) conducted a meta-analysis that showed probiotic supplementation reduced migraine frequency with mixed effects on severity whilst Kappéter et al. (2023) proposed fecal microbiota transplantation (FMT) as a means of microbial restoration and normalizing the inflammatory mediators implicated in migraine chronification. What does the CH literature say? Comparable findings in CH are absent however new evidence does show an emerging persistent inflammatory signature. In peripheral blood, Lund et al. (2025) found distinct cytokine profiles across all CH types with oncostatin M (OSM), an IL-6 family cytokine, elevated in cCH, eCH in-cycle and eCH in remission groups. In cerebrospinal fluid, Ran et al. (2024) demonstrated higher chemokine concentrations with a serum-to-CSF gradient, concentrating inflammation within the central nervous system (CNS) and present both during active cycle and remission periods. More recently, PACAP-38 has also been found to be elevated in CH compared with controls, further supporting the presence of sustained neuroimmune activation involving vasoactive peptides even during remission periods. And whilst an underlying inflammatory signature has now been identified, the upstream driver of these elevated markers remains unlinked to dysbiosis. Taken together however these new findings point to CH as a condition underpinned by ongoing inflammation within the CNS rather than a series of isolated pain events attributed to dysfunction of the hypothalamus. So, what was this about a diet? Sign me up! What has recently been referenced by myself and others in the CH community is a 2018 case-control study by Di Lorenzo et al. that examined the effects of a ketogenic diet in a small cohort of 18 chronic CH patients refractory to standard preventive treatments. The authors reported that 15 participants responded favorably, with 11 achieving sustained pain-free remission and 12 choosing to remain on the intervention even after the study concluded. Although the mechanism of action was not explored, it is my view that the therapeutic benefit of the ketogenic diet likely extends beyond the metabolic effects of ketone production to include modulation of the gut microbiota and its associated inflammatory milieu. To my knowledge, this remains the only dietary intervention in CH and while the sample size was small the findings were nonetheless remarkable. Here warrior – I recommend giving this a try... Consider this a brief pause, a half-time reflection, before moving into the following sections. Few examples illustrate the power of patient-led initiatives better than what the CH community has been able to achieve. Out of necessity and sheer persistence, patients have effectively conducted some of the most successful citizen science projects in existence. From the early work exploring psychedelic therapy to the development of the vitamin D3 anti-inflammatory regimen, each step has been driven by individuals determined to find solutions where few existed. These remarkable efforts have produced measurable results and practical treatment tools that continue to change the lives of CH patients, indeed not all heroes wear capes. Where vitamin D3 & psilocybin converge... What I find particularly intriguing is that both of these therapies, psychedelic compounds and the Vitamin D regimen, according to emerging research, may exert part of their therapeutic effect through interactions with the gut microbiota. At the same time, their variable efficacy from one CH patient to another may be influenced by the baseline state and diversity of that patient’s microbiome. This bidirectional relationship, in which treatment both shapes and is shaped by its interaction with the microbiota, may help explain why some experience complete remission while others achieve only partial or temporary relief, or require higher or repeated doses. In the following sections, I will examine the literature that highlights the potential points of convergence between Vitamin D and psilocybin, focusing on microbiome mediated interactions. Oh vitamin D3, you have been kind to me... For almost a decade now, the Vitamin D3 anti-inflammatory regimen has kept me mostly pain-free from CH. Beyond its role in calcium homeostasis Vitamin D3 plays a key role in maintaining gastrointestinal homeostasis. The active form, 1,25-dihydroxyvitamin D3, binds to the Vitamin D receptor (VDR), which is expressed throughout the intestinal epithelium and immune cells. Through this signaling pathway Vitamin D3 influences epithelial integrity, microbial diversity and modulates the immune response (Vemulapalli et al., 2025). In refining the original regimen, Pete Batcheller included a B-complex, taking inspiration from Gominak’s work linking Vitamin D restoration to improved sleep and gut function through the microbiota’s production of B vitamins (Gominak, 2016). Gominak proposes that both Vitamin D and the microbiota exist in a symbiotic relationship, where Vitamin D supports the host environment necessary for microbial balance while a healthy microbiota contributes to the production of essential cofactors necessary for neuronal and immune health. Charoennngam et al. (2020) demonstrated that Vitamin D3 supplementation shifts the microbiota toward a less inflammatory profile, increasing beneficial commensal species such as Bacteroides while reducing pathogenic species like Porphyromonas. In regards to maintenance of the epithelial membranes, Vitamin D3 upregulates tight-junction proteins such as claudins and occludins while lowering zonulin expression, a key marker for intestinal permeability. By strengthening tight junctions Vitamin D3 may limit translocation of bacterial endotoxins such as LPS into systemic circulation (Fedele et al., 2018; Stio et al., 2016). In addition to maintaining gut barrier integrity, Vitamin D3 modulates the immune response by inhibiting NF-κB activation and reducing the production of pro-inflammatory cytokines while supporting T regulatory cell function and the production of antimicrobial peptides such as cathelicidins and beta defensins (Vemulapalli et al., 2025). Taken together these findings place Vitamin D3 as a key mediator in gut-immune homeostasis, acting at the bleeding edge between the microbial landscape and host defense. Importantly, as demonstrated by Holick and colleagues in Scientific Reports (2019), the genomic actions of Vitamin D3 are dose and blood-level responsive with higher 25-hydroxy vitamin D levels resulting in broader transcriptional changes across hundreds of genes involved in immune regulation. The fact that Pete Batcheller’s regimen has been assembled into a simple and accessible protocol with consistently impressive response rates is in itself a remarkable achievement given the devastating nature of CH. Whilst Vitamin D3 almost certainly acts on receptors within the trigeminal ganglion and hypothalamus, these recent findings suggest its actions in the periphery, particularly within the gut, may play an important role in the therapeutic efficacy of the anti-inflammatory regimen. What can mushrooms possibly have to do with any of this? Intriguing new research suggests that the therapeutic effects of psychedelics, particularly psilocybin, may in part be mediated through interactions with the gut microbiota. While its best described actions involve modulation via the serotonergic receptor, new findings reveal that psilocybin also exerts systemic effects on inflammation, immune signaling, intestinal barrier integrity as well as shaping the microbial landscape itself. Wang et al. (2025) provide an elegant synthesis of this evolving concept in a recent ACS Chemical Neuroscience viewpoint, suggesting that the therapeutic effects of psychedelics including psilocybin extend beyond cortical serotonergic circuits to modulate the gut-brain axis via interactions with the microbiome. Building on emerging evidence they position these compounds as both neuroactive and immunomodulatory agents, potentially influencing inflammation along the microbiota-gut-brain pathway via NF-κB mediated cytokine modulation as shown in complementary models like Zanikov et al., 2024. Zanikov et al. (2024) were able to show in a mouse model of colitis that psilocybin reduced gut driven neuroinflammation and lowered the expression of inflammatory cytokines IL-1β, IL-6 and COX-2 in brain parenchyma. These findings link intestinal inflammation directly to a central inflammatory response and confirm that psilocybin’s anti-inflammatory effects occur along the gut-brain axis rather than within the brain alone. Complementary in vitro work in human macrophages shows dose dependent suppression of LPS induced cytokines via modulation of NF-κB signaling, highlighting its broad immunoregulatory potential. Kelly et al. (2023) introduced the term “psilocybiome” as a framework to describe the bidirectional relationship between psychedelics and the microbiota-gut-brain axis, they propose that microbial diversity and metabolism influence every phase of psychedelic therapy from preparation and acute experience to integration. Caspani et al. (2024) build on this by exploring psychedelics potential antimicrobial effects and how they may reshape gut ecology, suggesting that microbial composition modulates psychedelic pharmacokinetics while remarkably, psychedelics, in turn, remodel the microbiota. This research suggests that psilocybin’s therapeutic benefit may indeed depend on the baseline composition and inflammatory state of the gut microbiome. This perspective offers a fresh view for the variability in dose response observed within the CH community’s collective busting experiences. It appears reasonable to suspect that interventions which restore microbial balance and support gut integrity may enhance the therapeutic window for psychedelic therapy. Although the degree to which these microbial mediated mechanisms contribute to the therapeutic benefit we see in busting for CH remains speculative, these new findings make clear that psilocybin’s actions reach beyond the mind, extending into the intricate microbial terrain in a complex dance that is beginning to be revealed. So what about that case report? Recent clinical evidence provides an example of how restoring microbial homeostasis may be achieved through an integrative approach. A 2023 case report by Beltran and Guimarães described the successful treatment of a patient with psoriasis vulgaris refractory to conventional therapies using a combined anti-inflammatory diet, high-dose vitamin D3 therapy and targeted herbal antimicrobials. The case report used a diagnostic workup that included the Gastrointestinal Microbial Assay Plus (GI-MAP), a DNA-based stool test that identifies bacterial, fungal and parasitic taxa as well as markers of gut inflammation and intestinal permeability by Quantitative PCR (qPCR). This diagnostic framework provided a precision-based view of the patient’s baseline microbial state and guided subsequent therapeutic choices. Such testing reveals that, just as no two microbiomes are identical, one size may not fit all in nutritional or supplement interventions. Importantly, dysbiosis patterns and their immunological signatures vary between individuals which necessitates personalized modulation of the microbiota rather than blanket probiotic or dietary advice. In the specific case testing revealed small intestinal fungal overgrowth (SIFO) driven by Candida albicans. These results informed a selection of herbal antimicrobials, notably oregano oil for its antifungal and biofilm-disruptive properties. Oregano oil’s mechanisms include membrane disruption and inhibition of fungal enzyme activity which reduce microbial burden and help restore mucosal homeostasis. To complement this, Curcumin longa (turmeric) was used for its capacity to inhibit NF-κB-mediated inflammation and upregulate VDR expression in epithelial and immune cells. Following five months of intervention immunofluorescence analysis of VDR expression in skin biopsies revealed upregulation of receptor density compared with baseline, correlating in full clinical remission. This finding parallels the discussion advanced in Beltran’s companion paper, Vitamin D Receptor Renewal Through Anti-Inflammatory Diet, which identifies the suppression of VDR by LPS, mycotoxins and inflammatory cytokines as key drivers of vitamin D resistance in chronic inflammatory and autoimmune diseases. By resolving dysbiosis and improving epithelial integrity through diet, the intervention removed the upstream inflammatory blockade to VDR transcription and restored immune tolerance. Where and how to even conclude this...? Cluster headache, long regarded as the most devastating disorder, may find part of its explanation not in the brain alone but in the microbial world that indeed sustains it. As our understanding of the gut-brain-immune axis deepens, the concept that dysbiosis and intestinal permeability may act as upstream drivers of neuroinflammation becomes increasingly difficult to ignore. While the literature in CH remains in its infancy, speculative bridges are clearly already being built with patents having been filed for microbial modulating technologies aimed at treating headache disorders, such as US9987224B2, which describes methods for altering gut microbiota composition to influence neurological outcomes including migraine and CH. Such developments are another signal of the growing recognition that modulating our microbial landscape presents as an attractive therapeutic target for disorders once considered purely neurogenic in origin. All being said, it's early days – what I think we have is an interesting hypothesis more so than settled science for CH specifically. The ketogenic results are impressive but need larger, controlled trials; vitamin D3 works for many but the anti-inflammatory regimen remains without clinical validation in CH and psilocybin's ties to the microbiome are certainly intriguing but mostly preclinical. All three treatment options are available for patients to pursue at their own discretion. I hope I have been able to articulate my take on the current literature and of course welcome your thoughts, comments and ideas. I have tried to be as accurate as possible, please point out any shortcomings. Many questions remain covering other important topics in CH such as genetics, periodicity and the role of personality; still – I feel like it is an exciting and hopeful time and look forward to seeing what future research may show in regards CH and the microbiome. References Migraine Vuralli, D., Akgör, M.C., Gök Dağıdır, H. et al. (2024) ‘Lipopolysaccharide, VE-cadherin, HMGB1 and HIF-1α are elevated in chronic migraine with MOH: evidence of leaky gut/inflammation’, J Headache Pain. Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC10875763/ He, Q., Zhang, Y. and Li, R. (2023) ‘A causal effects of gut microbiota in the development of migraine’, J Headache Pain. Link: https://thejournalofheadacheandpain.biomedcentral.com/... Grodzka, O. and Domitrz, I. (2025) ‘Gut microbiota, probiotics, and migraine: a clinical review and meta-analysis’, Journal of Oral & Facial Pain and Headache. Link (journal): https://www.jofph.com/articles/10.22514/jofph.2025.043 Kappéter, Á., Zając, A., Domitrz, I. (2023) ‘Migraine as a disease associated with dysbiosis and possible therapy with fecal microbiota transplantation’, Biomedicines. Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC10458656/ Cluster Headache Lund, N.L.T., Pedersen, S.H., Ashina, M. et al. (2025) ‘Distinct alterations of inflammatory biomarkers in cluster headache: a case–control study’, Annals of Neurology. Link (journal): https://onlinelibrary.wiley.com/doi/10.1002/ana.27205 Ran, C., Yang, Y., Guo, S. et al. (2024) ‘Elevated cytokine levels in the central nervous system of patients with cluster headache’, J Headache Pain. Link: https://thejournalofheadacheandpain.biomedcentral.com/... Søborg, M.L.K., Amin, F.M., Ashina, M. et al. (2025) ‘PACAP-38 in cluster headache: a prospective, case-control study of a potential treatment target’, Eur J Neurol. Link (PubMed): https://pubmed.ncbi.nlm.nih.gov/41002104/ Ketogenic Diet Di Lorenzo, C., Coppola, G., Sirianni, G. et al. (2018) ‘Efficacy of Modified Atkins Ketogenic Diet in Chronic Cluster Headache: An Open-Label, Single-Arm Clinical Trial’, Frontiers in Neurology. Link: https://www.frontiersin.org/.../10.../fneur.2018.00064/full Vitamin D3 Vemulapalli, R., Thomas, A. (2025) ‘The Role of Vitamin D in Gastrointestinal Homeostasis and Gut Inflammation.’, Int. J. Molecular Sciences Link: https://pubmed.ncbi.nlm.nih.gov/40243631/ Gominak, S.C. (2016) ‘Vitamin D deficiency changes the intestinal microbiome reducing B-vitamin production in the host: a hypothesis explaining chronic sleep disorder’, Medical Hypotheses. Link (PubMed): https://pubmed.ncbi.nlm.nih.gov/27515213/ Charoenngam, N., Shirvani, A., Holick, M.F. (2020) ‘The Effect of Various Doses of Oral Vitamin D3 Supplementation on Gut Microbiota in Healthy Adults: A Randomized, Double-blinded, Dose-response Study’, Anticancer Research. Link: https://pubmed.ncbi.nlm.nih.gov/31892611/ Stio, M. et al. (2016) ‘Vitamin D regulates the tight-junction protein expression in active ulcerative colitis’, Scand J Gastroenterol. Link (PubMed): https://pubmed.ncbi.nlm.nih.gov/27207502/ Scricciolo A, Roncoroni L, Lombardo V,Ferretti F, Doneda L,Elli L (2018) ‘Vitamin D3 Versus Gliadin: A Battle to the Last Tight Junction’, Digestive Diseases and Sciences. Link: https://pubmed.ncbi.nlm.nih.gov/29159680/ Shirvani A, Kalajian TA, Song A, Holick MF. (2019) ‘Disassociation of vitamin D’s calcemic and non-calcemic genomic activity & individual responsiveness: RCT’, Scientific Reports. Link: https://www.nature.com/articles/s41598-019-53864-1 Psychedelics Wang, X., Li, H. and Zhou, Z. (2025) ‘Psychedelics and the Gut Microbiome: Unraveling the Interplay and Therapeutic Implication’ (Viewpoint), ACS Chemical Neuroscience. Link (journal page): https://pubs.acs.org/doi/abs/10.1021/acschemneuro.5c00418 Zanikov, T., Gerasymchuk, M. and Robinson, G.I. (2024) ‘Psilocybin and eugenol prevent DSS-induced neuroinflammation in mice’, Biocatalysis and Agricultural Biotechnology. Link: https://www.sciencedirect.com/.../pii/S1878818124000161 Caspani et al. (2024) ‘Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis’, Progress in Neuro-Psychopharmacology & Biological Psychiatry. Link: https://www.sciencedirect.com/.../pii/S1043661824002834 Kelly, J.R., and Clarke, G. (2023) ‘Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis’, International Journal of Psychopharmacology Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC9791138/ Case Report & Other Beltran, E.P. and Guimarães, G. (2023) ‘High-dose vitamin D3, anti-inflammatory diet and targeted antimicrobials in psoriasis vulgaris: clinical case with VDR immunofluorescence’, Zenodo case report (grey literature). Link: https://zenodo.org/record/7799594 Beltran, E.P. (2023) ‘Vitamin D Receptor Renewal Through Anti-inflammatory Diet’, ResearchGate/Institutional page (grey literature). Link: https://www.researchgate.net/.../369801068_Vitamin_D... US 9,987,224 B2 (2018) ‘Method and system for preventing migraine headaches, cluster headaches and dizziness.’ Link (Google Patents): https://patents.google.com/patent/US9987224B2/en

Hi CHfather - thanks for stopping in. This is the first case series I am aware of looking at a gepant and CH, in this case Qulipta / Atogepant. There is a trial looking at Nurtec / Rimegepant as a preventative therapy for CH. Ubrelvy / Ubrogepant is more an acute treatment owing to short half-life makes preventive use impractical and may not act quickly enough for acute CH attacks. I haven't read anything about the third generation gepant Zavegepant, again an acute treatment via nasal spray. I haven't really followed patient feedback on any them tbh. I think this case series, if anything, may provide some context for clinicians considering where to next for refractory CH patients non-responsive to other treatments, including anti-CGRP mAbs like Emgality / Galcanezumab - this suggests that atogepant may be worth a try. I imagine there may be a tendency to think if a mAb hasn't previously worked or stopped working as was the case for one of the cases, a gepant is unlikely to either. That being said, ya'll know I have had success with the vitamin D3 anti-inflammatory regimen and my personal view would be to exhaust the patient led treatments options that we have (busting + regimen) paired with abortives (oxygen and more recently DMT) before considering one of these new treatments because I am somewhat adverse to risk and there is no long term clinical data on their safety. For refractory patients for whom my heart truly aches, this may offer some hope - still, an early signal and a small case series.

Here is a screenshot from one of the authors posts on LinkedIn. The research coming out of the Danish Headache Center is outstanding, I have recently shared the findings of their paper identifying the distinct cytokine profiles that distinguish eCH from cCH and also found that Oncostatin M was elevated in all 3 CH states.

PACAP-38 in Cluster Headache: A Prospective, Case–Control Study of a Potential Treatment Target Marie-Louise K. Søborg, Nunu Lund, Agneta Snoer, Mads Barloese, Rigmor Højland Jensen, Anja Sofie Petersen Published in European Journal of Neurology on September 26, 2025 Link: https://doi.org/10.1111/ene.70341 Abstract: (partial selection) This large-scale study demonstrated increased PACAP-38 levels in all disease states of cluster headache compared to headache-free controls, strengthening the hope of a possible effect of PACAP-38 targeting treatments in future trials. The lacking correlation between PACAP-38 and CGRP levels should be interpreted with caution and needs to be investigated in future studies.

Can atogepant be a preventive treatment for cluster headache?-Insights from a case series Catarina Serrão, Filipa Dourado Sotero, Linda Azevedo Kaupilla, Isabel Pavão Martins Published in Headache on October 3, 2025 Link: https://doi.org/10.1111/head.15066 Abstract: Cluster headache (CH) is a disabling primary headache disorder with limited therapeutic options. Calcitonin gene-related peptide (CGRP) is known to be involved in CH pathophysiology; however, except for galcanezumab (300 mg) in episodic CH, anti-CGRP monoclonal antibodies did not reduce CH attacks in randomized clinical trials. Atogepant is an oral, small-molecule, CGRP receptor antagonist, which is approved for the preventive treatment of migraine. Here, we describe four case reports of CH (two episodic CH and two chronic CH), unresponsive to previous prophylactic treatments, who responded to daily atogepant (60 mg). Chronic CH cases were refractory to subcutaneous galcanezumab. In one case, a reduction to atogepant (30 mg daily) resulted in recurrence of headache attacks, which subsided on reintroduction of the initial dose. No serious adverse effects were reported. Despite the limited number of cases and the open retrospective design, our case series suggests atogepant as a possible prophylactic treatment for CH. Further research on CGRP signaling in CH and the implementation of well-designed clinical trials are necessary.

ABSTRACT: Classic psychedelics and the gut microbiome interact bidirectionally through mechanisms involving 5-HT2A receptor signaling, neuroplasticity, and microbial metabolism. This viewpoint highlights how psychedelics may reshape microbiota and how microbes influence psychedelic efficacy, proposing microbiome-informed strategies such as probiotics or dietary interventions to personalize and enhance psychedelic-based mental health therapies. Psychedelics and the Gut Microbiome: Unraveling the Interplay and Therapeutic Implications https://pubs.acs.org/doi/abs/10.1021/acschemneuro.5c00418 A fascinating new view-piece synthesizing the current literature exploring psychedelic / gut / microbiome interaction in the context of depression. Wang and colleagues emphasise that "the baseline composition and functional state of the microbiome can shape psychedelic pharmacology and therapeutic efficacy, while the psychedelic experience itself can remodel the gut microbiome in ways that influence ongoing physiological and psychological adaptation." At the cellular level they note psychedelics suppress the production of pro-inflammatory cytokines IL-6 and TNF-α through 5-HT2A receptor-mediated inhibition of NF-κB signalling: "this immunomodulatory action establishes an anti-inflammatory milieu that favors the growth of beneficial commensal bacteria." Compounds such as psilocybin and DMT "reduce pro-inflammatory cytokine expression and enhance epithelial barrier integrity, promoting the expansion of anti-inflammatory taxa." They note, the microbiome is not a passive bystander: "gut bacteria express a variety of enzymes capable of biotransforming these substances, thereby shaping their pharmacokinetic profiles. For instance, Bifidobacterium species have been shown to affect the metabolism of DMT, potentially altering the intensity and duration of ayahuasca experiences. Similarly, in vitro studies have identified bacterial strains that dephosphorylate psilocybin into its active form, psilocin, suggesting that individual differences in microbiota composition may underlie variability in therapeutic response." Wang et al. refer early human data noting that "although human studies remain limited, early observations suggest that psychedelic treatment may be associated with alterations in fecal microbial diversity in patients with depression." These observations support what the authors call a "systems-level perspective of psychedelic therapy - one that encompasses not only neural targets but also immunological, endocrine, and microbial domains." The article is behind a paywall, send me a message if you'd like a copy of the article. For more reading the article cites this paper "Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis" https://pmc.ncbi.nlm.nih.gov/articles/PMC9791138/ In the context of CH, with new evidence of persistent immune-inflammatory activity suggests psychedelic therapy not as acting solely on the brain but by potentially intersecting with the upstream gut-barrier-immune processes that maintain systemic inflammation that are now attributed as a causative agent in migraine. The paper also goes some way to positing a possible reason for the variations we see in busting efficacy. This area of research is fascinating and I think the piece provides a further and new angle as to the role gut health may play in CH alongside recent findings in migraine although there is much road to travel before we have any concrete evidence of this. Still mulling my thoughts, all I offer here is a view - always interested in yours. With respect, Craig.

Hi all. I wanted to build on a post couple of months back that mentioned this early 2025 study in Annals of Neurology which found that Oncostatin M (OSM) was significantly elevated across all forms of cluster headache (CH), episodic in cycle (ECH), episodic in remission and chronic (CCH) when compared with controls. Distinct Alterations of Inflammatory Biomarkers in Cluster Headache Lund, N. L. T. et al. Annals of Neurology. 2025 https://pubmed.ncbi.nlm.nih.gov/39981939/ Interpretation: Findings show that the immune system is altered in all 3 states of cluster headache compared with controls. Oncostatin m was elevated, constituting a promising target for future studies. The distinct alterations between episodic and chronic cluster headache are striking and urges further research of the immune system in cluster headache to better understand its potential role in prediction of disease activity and treatment response. OSM belongs to the interleukin-6 family of cytokines which are signalling molecules released by cells to facilitate communication within the immune system and the body, acting as messengers and binding to receptors on other cells to trigger responses like inflammation, cell growth and immune cell activation. OSM is produced mostly by activated monocytes and macrophages along with T-cells once the immune system is already engaged. Triggers include microbial products such as lipopolysaccharide acting on toll-like receptors, upstream cytokines like IL-1β, TNF-α, and IL-6 as well as T-cell activation itself. In other words OSM typically appears as a second-wave signal once innate and adaptive cues are already active. After its release OSM signals through receptor complexes that require gp130 subunit, a shared hub for the IL-6 family. OSM pairs gp130 with either OSMR or LIFR receptors which activate Janus kinase enzymes (JAKs). JAKs phosphorylate STAT3 (signal transducer and activator of transcription 3) and activated STAT3 then enters the nucleus to upregulate genes for chemokines, adhesion molecules and matrix metalloproteinases. Short-term controlled activation of this pathway is essential for tissue repair but sustained persistent activation may lead to detrimental effects including weakened barriers, leukocyte recruitment and ongoing systemic inflammation. In Crohn’s disease and ulcerative colitis OSM has been shown to drive stromal activation and barrier dysfunction and high levels of OSM are a predictor of poor response to anti-TNF-α therapies. The CH study by Lund and colleagues suggests a similar kind of hard-to-quiet inflammatory program in the cranial milieu of CH patients regardless of whether or not they are in active cycle. So what may drive the persistent upstream activation that induces OSM in the first place? This wasn't discussed in the article but one source that may deserve attention is the emerging gut-immune-brain axis. As explored in my earlier post, a growing body of literature in migraine describes altered gut and oral microbiota, reduced microbial diversity, links to markers of intestinal hyperpermeability and bacterial endotoxin exposure as causative agents in migraine pathology. While migraine and CH are distinct disorders both share neuroinflammatory components, cytokine involvement and respond to many of the same treatments, is it reasonable to ask whether dysbiosis may help maintain the triggers that induce OSM expression? And if so what implication does that have on future treatment strategies for CH? And where might the Vitamin D regimen fit into this picture? The active form of Vitamin D, calcitriol, binds to the vitamin D receptor in immune and barrier cells and influences the expression of hundreds of genes. It suppresses NF-κB and MAPK signalling, promotes regulatory T-cells and IL-10 and strengthens barrier integrity by upregulating tight junction proteins in epithelial and endothelial cells. Building on Pete Batcheller’s hypothesis, maintaining sufficient blood levels of Vitamin D3 may help downregulate some of the upstream drivers of OSM expression while counteracting OSM’s disruptive effects on barrier function. Supporting this idea, work outside the headache field has shown that calcitriol can shift macrophages from an M1 pro-inflammatory state toward an M2 reparative state, reducing the production of OSM, TNF-α, and IL-6. A balanced view is important. The 2025 study identifies OSM as a persistent signal and points to specific differences between chronic and episodic CH. It did not identify a cause and it did not test interventions. The migraine-microbiome literature suggests dysbiosis as one possible upstream driver but translation to CH is yet to be explored. Other papers from this author on CH for your interest. https://pubmed.ncbi.nlm.nih.gov/?term=Lund+NLT&cauthor_id=37667192 Includes an article titled "Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article" which concludes "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."

Welcome, sorry you had to find us but glad you found CB. I had a chuckle at Shaun’s comment but I would agree we are a lovely but mad bunch. I am sure you’ll get the support you need here. I’d be another of the replies to encourage you to investigate the vitamin D3 anti-inflammatory regimen; has worked beautifully for me with eCH.

Hi all. I saw a post recently from a fellow CH warrior that designed and built a CH tracker app. Heres the link: https://clusterheadachetracker.com I believe it may be in beta test mode but love the ingenuity and skill in our amazing community.

Hi all. Here's an interesting new preprint "Autonomic dysfunction in patients with episodic cluster headache during remission period". This study looked into the autonomic nervous system in an episodic cluster headache cohort during their pain-free remission periods. They found a significant decrease in Heart Rate Variability (HRV) in CH patients compared to controls, this lower HRV suggesting a sympathetic predominance / reduced parasympathetic activity. CH patients also had a higher mean heart rate and significantly higher plasma norepinephrine levels both when lying down and standing which indicates increased sympathetic activity. This study suggests an ANS imbalance in CH even during remission pointing to a decrease in parasympathetic activity and sympathetic hyperactivity. They call for more research. This also makes me consider the value of, I believe the term is non invasive vagus nerve stimulators via devices like the Gammacore and others like the Pulsetto. The latter being fairly affordable although requires a level of consistent daily use to see the benefit it promotes, one of which was an increase in HRV. Full disclosure, I have a Pulsetto but being in remission and busy I don’t use it frequently enough to offer any meaningful feedback other than to say the sensation is funky at first but you get used to it. You can find the full preprint here: https://www.researchsquare.com/article/rs-6871540/v1

Sleeps an interesting thing! Sorry if it was mentioned but how are you measuring, a smart watch or such? Good on you for tracking, super cool what tech can do. This article was published, I’ve only glimpsed the review but based on above you may find it interesting. Not a specific CH sleep study but CH is reviewed in the context of arousal & CGRP. It also looks at microbiome research and sleep. I had this set aside for this weekend to read, will come back and share further thoughts once I’ve digested it. Orofacial pain/headache interlaced to insomnia, sleep apnea and periodic limb movement during sleep/restless leg syndrome: a critical and comprehensive review with insights into social determinants https://files.jofph.com/files/article/20250612-403/pdf/OFPH20241219001.pdf

Thanks CHfather, I have updated the poll to ask the question and record if the person is a sufferer or not and if so, what form. I take it you added your email and received the analysis run through the prompt - it's just sending your results via an automation to a model with a prompt to analyse them - the prompt deals with a tie in scores based on prioritizing CH traits and if a tie stills exists, rank in alphabetical order - I have made that now clear in the email summary. Thanks for sharing these studies! Raises more questions than answers. Significant that the observed craniometric abnormalities were independent of smoke and alcohol intake which contrasts previous hypotheses that lifestyle factors might explain facial features like the "leonine face" that Graham and Kudrow wrote about. We also have a new paper published a few days back - Smoking in primary headaches – a systematic review and meta-analysis looking at smoking in primary headaches and found a weighted-pooled prevalence of smoking in CH patients of 65% being the highest prevalence among primary headache types evaluated, compared to 20% for migraine and 19% for TTH. Despite this they concluded that current smoking was not associated with CH diagnosis when compared to controls and suggest this lack of association might be due to the limited number of studies included for CH in their meta-analysis but also state that while smoking is commonly associated with CH, it may result from other as yet unidentified factors which aligns with the 2021 craniometry study's finding that the observed bone abnormalities are independent of smoking and alcohol consumption. On the losing beloved family pets, oh man it's tough. I'm sorry. We lost Harper our female border collie at 9 maybe 2 years back, Ollie held tough, my loyal mate, for another couple of years and he enjoyed great health over his 15 years with me. The sharpness of the pain has subsided but boy do I miss him, I find myself telling "Gurl" that Ollie would have adored her, he got so excited around cats. Cats are so different, try and approach them they run away, ignore them and they come to you. Alas its my Sunday and I have one very important task to do today, and that is book flights to Dallas for September. We are very excited but trying to figure out how much time to spend exploring Dallas and maybe Austin before going upto Seattle. It's a long old flight to not make the most of it - 24 hours, ungh.

Here guys - take the Salamanca test - after taking the poll via a Google form you can see the google sheet. Its anonymous. Enter your email only if you want to receive a summary of your scores. If it looks interesting enough I might share it on FB to get some decent numbers. Give me some feedback before I do. https://forms.gle/3THW4dYdRLShLgJi8 The questions are pretty out there in this test, bearing in mind its translated from I think Spanish. "I am more in touch with the paranormal than most people" an example of a question I am unsure as to how may be influenced by having CH. Given I grew up watching Mulder and Scully afterschool on rerun I scored pretty high on that one. @CHfather @BoscoPiko @Bejeeber You know there is an obvious trend on the CB forum where members enlist a feline as their profile picture. Maybe I missed the memo. I have never been a cat guy - I lost my 15yr old black and white border collie Ollie a few months back and the very next day after his passing, a little black and white girl started hanging at the back door. It looked dishevelled. Had a broken tail. It was hungry. We didn't know the hard and fast rule so yes, we fed it. Yes, it stayed. Yes, every night I think I can hear my neighbours kid wailing themselves to sleep but there you go, I'm also now a cat guy so maybe I snap a quick pic and get rid of my profile mugshot. @Alx Believe it was the late John R Graham that came up with the rugged face and skin of the CH sufferer in the 1970s. Those papers were pretty wild, - a different time - from his 1974 article CH, "Male patients are frequently brought to the physician by the wife, who also takes the prescriptions and makes the telephone calls and appointments for her husky suffering mate, leading to the terminology "the leonine mouse syndrome." Episodes of hysterical behavior, amnesia, fugues, transvestism, overt homosexuality, and psychotic breaks have occurred in some patients."

Greetings all, It’s been a hot minute since I last thought about the intersection of personality profiles and CH but a recent literature dive brought it back into focus, unintentionally I might add. I don’t know if you’ve come across a tool called Harzing’s Publish or Perish, it makes searching the scientific literature super easy. Using it I stumbled upon a 2016 paper that struck a chord over the past couple days and I wanted to share it here. I want to say before you read further there was an element of reading this study that was triggering / confronting so I just wanted to make that disclosure - this can be a challenging topic to navigate. Personality traits in patients with cluster headache: a comparison with migraine patients https://pmc.ncbi.nlm.nih.gov/articles/PMC4791411/ According to the Salamanca screening test, personality traits included in cluster A (odd or eccentric disorders) are more prevalent in CH patients than in a population of migraineurs. Larger studies are needed to determine whether certain personality traits are related to CH. The study compared 80 CH sufferers (mostly male, average age 43) with 164 migraine patients (mostly female, average age 36). Using the Salamanca screening test, they found the most common traits in the CH group were: Anancastic (52.5%) Anxious (47.5%) Histrionic (45%) Schizoid (42.5%) Impulsive (32.5%) Paranoid (30%) Compared to migraineurs, paranoid and schizoid traits were significantly more common in CH sufferers. According to this screening tool, Cluster A traits (odd or eccentric personalities) appear more common in CH patients than in migraine patients. I was curious enough to simulate the Salamanca test using a language model and, no surprise, I scored highly on the same cluster: anancastic/OCPD, anxiety-related and schizoid traits. I did not score highly in the histrionic traits. Here’s a brief overview of what the 2 of these personality patterns look like that were pertinent for me, starting with anancastic (also known as Obsessive-Compulsive Personality Disorder, which is distinct from OCD). Anancastic was a new term for me, I hadn't heard of it before: Anancastic Traits (OCPD) Preoccupied with rules, structure, and control Perfectionism that interferes with task completion Rigid thinking, especially around morality Workaholic tendencies at the expense of relationships Difficulty delegating due to high standards Hoarding or excessive saving Stubbornness and resistance to change I score fairly solid on that one, lol. I look at the list and recognize a number of things that I consider work-on's in my life, balance between work and social relationships being one of them; real estate is not a great choice for that I must say. Definitely rigid in my thinking around morality, I wish I was an excessive saver(!!!) and I like tradition, I am not fond of change. And then there’s schizoid which frankly the word has a certain connotation to it but putting that aside: Schizoid Traits Strong preference for solitude Emotionally flat or detached Disinterest in close relationships, including family Limited enjoyment from most activities Unmoved by praise or criticism Few or no close friends or confidants The last time I had really delved into the above traits was to explore one of the other topics of my podcast, fatherlessness - Freud wrote about some of these qualities in Mourning and Melancholia. I was surprised to see some of those traits appear in this study. I have often wondered what bearing early parental loss had in the context of my CH, again difficult to explore because the discussion is contextual, there's no hard and fast with such abstract subjects albeit I have little doubt that early life adversity played a part in my journey with CH. Alas, if you’ve ever felt a bit “wired differently” or found it hard to relate to the social world most people seem to navigate with ease, this study suggests you may not be alone. It’s fascinating and maybe even a little validating to see how certain personality traits appear more frequently among cluster headache sufferers. It raises further discussion points. Are these traits a product of the pain, isolation and the unpredictability of CH? Or is there a deeper neurological or biological predisposition at play? My wife also took the test and didn't score for these results. I could setup an anonymized poll via a Google sheet if there was interest - equally interested in your thoughts as always. Craigo.