Craigo

Faraidoon is the headache researcher whom is leading the Psilocybin Efficacy and Acceptability on Cluster headache Episodes (PEACE) Trial.

Patient perspectives on research gaps in cluster headache Faraidoon Haghdoost, Dilara Bahceci, Candice Delcourt, Tissa Wijeratne, Rigmor H Jensen, Carl Cincinnato, Susan Tomlinson, Bob Wold, Vince Polito, Cheryl Carcel, Usman Ashraf, Bronwyn Jenkins, Anja Sofie Petersen, Jason C Ray, Emmanuelle A D Schindler, Benjamin Tsang, Chris Gianacas, Anthony Rodgers Published in Headache on January 21, 2026 Link: https://doi.org/10.1111/head.70031 Abstract: Objective: This study was undertaken to identify gaps in cluster headache management, highlight patient-prioritized research needs, and assess patient interest in, and preferences for, clinical trial participation.

Most of these studies were posted here on the forum, study by study over the course of 2025. For those wanting to look at some of the studies mentioned they are in my 2025 CH Research Notebook.

2025 Highlights in cluster headache Roemer B. Brandt, Rolf Fronczek Published in Cephalalgia on January 2026 Link: https://doi.org/10.1177/03331024251411870 Abstract: Cluster headache remains enigmatic with a significant unmet treatment need, especially in the chronic form. The steps made in 2025 have taken us further along the road to a true understanding of the still unknown pathophysiology, hopefully leading to a causal treatment.

This is a pretty epic study and I have a lot of questions. I am not even sure I fully understand all of it yet, so I want to check that I am interpreting it correctly. Anyone else have any thoughts, please share. In their bidirectional Mendelian randomization analysis, are they essentially saying that they identified 11 cerebrospinal fluid metabolites that are associated with increased risk of cluster headache, and that among those, three showed the strongest associations, and these key metabolites are involved in pathways linked to mitochondrial energy metabolism and ATP production? Rather than mitochondria in cluster headache fail to produce enough ATP, it appears they are suggesting that ATP production is inefficient and metabolically costly. Do these findings help explain the small ketogenic diet study from 2018, where 11 of 18 refractory chronic cluster headache patients became pain free? There is often discussion about ketone bodies being a more efficient fuel source than glucose metabolism. In the context of this paper, could ketosis be improving ATP yield per unit of oxygen or reducing oxidative and redox burden on already stressed mitochondria, thereby raising the threshold for attack generation? What do these results suggest about the role of the “Full Monty” supplements that are recommended for non-responders to the base Vitamin D regimen? Many of those supplements have antioxidant or reactive oxygen species scavenging properties. Does this metabolite profile support the idea that reducing oxidative stress and the ATP cost of redox maintenance could improve mitochondrial efficiency and help explain why some non-responders improve when these additional supplements are introduced? The paper also references the glutathione cycle. Does the signal around 5-oxoproline and glutathione metabolism suggest that supplementing glutathione might be beneficial in this context? Or is the implication more that excessive glutathione turnover reflects an upstream oxidative burden that needs to be addressed rather than simply supplying more? What do these findings imply about the role of melatonin? Melatonin is synthesized within mitochondria and is known to improve mitochondrial efficiency, reduce oxidative stress, and support electron transport chain function. Could impaired or mistimed melatonin signaling be one of the factors that lowers energetic resilience during vulnerable circadian windows in cluster headache? Finally, do these findings offer any insight into a potential abortive mechanism for DMT? Anyone have any insight in this regard?

NotebookLM Audio Summary. Cluster_Headache_s_Metabolic_Root_Cause_Found.m4a Or just check out the Notebook for yourself. https://notebooklm.google.com/notebook/27364f47-4518-433b-86d9-d3aad07c9f0e?authuser=1

Bidirectional Mendelian Randomization Analysis of 338 Cerebrospinal-Fluid Metabolites and Cluster-Headache Risk Danhua Yu, Xuewei Yang, Jinli Zhou, Weiwei Chen, Jinhui Song, Weifei Yu & Shaokang Huang Published in Journal of Pain Research on January 8, 2026 Link: https://doi.org/10.2147/JPR.S550160 Abstract: Cluster headache (CH) is a rare but highly disabling primary headache disorder characterized by severe unilateral attacks and autonomic symptoms. The metabolic mechanisms underlying CH remain poorly understood. To investigate the potential causal effects of cerebrospinal fluid (CSF) metabolite levels on CH risk, and to explore possible reverse causal effects of CH on CSF metabolites, using a bidirectional Mendelian randomization (MR) approach. We performed a bidirectional two-sample Mendelian randomization (MR) analysis integrating genome-wide association study (GWAS) data for 338 cerebrospinal fluid (CSF) metabolites and CH (1,833 cases and 498,515 controls from FinnGen release 12). Genetic instruments were selected at P < 1×10−5 (LD r2 < 0.01). The primary causal estimates were derived using the inverse-variance weighted (IVW) method under a random-effects model, complemented by MR-Egger, weighted median, and MR-PRESSO sensitivity tests. Multiple testing correction was performed using both Bonferroni and false discovery rate (FDR) approaches. In the forward MR analysis, 11 CSF metabolites were significantly associated with CH risk (P<0.05). The strongest associations were observed for orotate (β = 0.53, 95% CI: 0.23–0.82, P = 0.0006), betaine (β = 0.47, 95% CI: 0.16–0.79, P = 0.0035), and 5-oxoproline (β = 0.57, 95% CI: 0.17–0.97, P = 0.0053). In the reverse MR analysis, eight metabolites, including lysine (β = 0.015, P = 0.029) and kynurenine (β = 0.025, P = 0.020), were nominally associated with genetic liability to CH. Sensitivity analyses showed no evidence of directional pleiotropy or heterogeneity (all P > 0.05). This bidirectional MR study provides the first genetic evidence linking central metabolic alterations to CH susceptibility. While these results highlight potential metabolic biomarkers and mechanistic pathways, the findings remain preliminary due to modest statistical power and should be replicated in larger and ethnically diverse cohorts.

Your post hits me in the feels. It really does. I would say it is changing lives. I have had one of those days, your post is timely and let me be as real as I can with you on what is a topic that lies close to my heart. At least once, more often several times a week, I receive an email from someone who found www.vitamindregimen.com, come across Clusterbusters, a social site or watched one of the interviews with Pete Batcheller on YouTube. They rolled the dice on the regimen and got pain free. They write to say it changed their life. Even one of those emails is enough to justify every hour of advocacy. It’s worth it. I have spent over a decade now reading obsessively on this topic, not just to understand why and how the regimen may work, but to also understand why a percentage of people do not get fully pain free when applying it. Along the way I have interviewed some of the most amazing people in the vitamin D3 research space and with every interview, every study read, every question asked, I feel like I have moved a little closer to an answer and built upon my knowledge of the subject. I am so grateful Pete opened that door for me. That man is a global treasure. It’s also perplexing because this week alone I have seen cluster headache social media channels suggest ginger, purple cabbage, and today, chewing on a lime. I should have become a fruiterer! I understand the premise behind criticism of the regimen or pushing it to the side as a bunch of simple pills. From the outside, a handful of vitamins can look just as batshit crazy as cabbage when stacked against the sheer terror of CH. I get it. That is the real challenge. How do you communicate the regimen in a way that reaches more people, without overclaiming, without slipping into evangelism and without being lumped into the bucket of folk remedies? How do you communicate something that sits uncomfortably between patient-led discovery and clinical blind spots? I may have an opportunity to do more having just resigned my job today with no intention of continuing on the same path / career. 43, soon to be jobless - very tempting to study and see what further value I may add to this important body of work. Never too old right? Absolutely agree with you, happy for you to have found success with it and pleased to see you here on the CB forums!

Dang, darn and I'm sorry you are getting hit despite the comprehensive approach you've got going on there. Quercetin and resveratrol were two of the primary anti-histamine full monty supplements in the regimen that come to mind, I didn't see that you had incorporated. It also suggests to increase the fish oil dosage. Just listing the items from the QSG below along with the suggested dosages. Primary Antihistamine Supplements A. 1 to 2 Grams/day Turmeric (Curcumin) with Piperine B. 1 to 2 Grams/day Quercetin C. 1 to 2 Grams/day Resveratrol D. 8 Grams/day vitamin C Optional As Needed E. 2 Grams/day Omega-3 Fish Oil (EPA and DHA) F. 250 mcg/day Selenium G. 1000 mg/day N-Acetyl Cysteine (NAC) H. 5 to 10 mg/day Melatonin (Taken at bedtime) I. 200 to 500 mg/day CoQ10 J. 50 mg Zinc Picolinate* K. Diamine Oxidase (DO)** 4 mg 2 to 3 times/day with meals Have you considered putting yourself into nutritional ketosis? In terms of a dietary measure that has some reports in chronic CH albeit was a small cohort 11 of 15 got pain free, the regimen quick start guide recommends it. I take it you have the quick start guide handy, if not it is here. There may be some relevant information there (page 12 onwards describes falling from remission / non-response to regimen). Other reports of nutraceuticals include thiamine which I had seen a few reports recently on Reddit threads of people reporting success but only a single case report in literature using 750mg (tapered). There is busting... a topic well covered on the forums, if an option for you? You probably already know you've got some medication options but just putting it out there, perhaps a short steroid course would be enough to disrupt the cycle and for it not to return after the taper? This was my go to for the first couple of years with the regimen (having not stayed on maintenance thereafter all year round). Or another poster pointed out a monoclonal antibody, there's also verapamil etc. Nothing it seems works for everyone but while you are throwing everything but the kitchen sink at it already I could only but list the options... I've only been in your position once before and at a baseline 100ng/mL and getting hit with attacks. I did another 600,000iu loading dose, all of the full monty supplements (less the melatonin), did NOT do keto and found myself pain free 4 days later - I realize I am lucky. I finished the load and dropped to 20,000iu maintenance for remainder cycle, level increased to 180ng/mL, calcium was okay - understandably becomes a bit nerve racking at these levels. Pete's labs in the guide show he has been higher than this previously - obviously none of us can flat out recommend you do that. Good luck I am sorry again you find yourself in that spot. XXX isn't too frequent here these days, if you DM me I am happy to share his email address should you want to drop him a line - hint, it's also listed on the bottom of the full reference guide.

Advancements in Intranasal Delivery of Drugs for Cluster Headache Treatment using Cubosome-Based Nanocarriers: A Review Preeti Chaudhary, Kirtan Vimal Shah, Darshan Rajendra Bodas, Sanjana Prasad Deshmukh, Akash Milind Solanki Published in Research Journal of Pharmacy and Technology on December 1, 2025 Link: https://doi.org/10.52711/0974-360X.2025.00887 Abstract: Cluster headaches (CH) represent a debilitating neurological disorder characterized by severe, recurrent attacks of pain, often leading to significant impairment in quality of life. Traditional treatments often face issues like delayed onset of action, systemic side effects, and challenges in achieving optimal drug concentrations at the target site. Intranasal drug delivery has emerged as a promising alternative for the management of cluster headaches due to its potential for rapid absorption and direct access to the central nervous system. Among the novel strategies under investigation, cubosome-based nanocarriers have gained significant attention due to their unique structural properties, biocompatibility, and ability to encapsulate a wide range of therapeutic agents. This review highlights recent advancements in intranasal delivery systems, focusing on cubosome-based nanocarriers for the treatment of cluster headaches. It explores the physicochemical characteristics of cubosomes that make them ideal for intranasal administration, including their high surface area, mucoadhesive properties, and ability to enhance drug stability and bioavailability. The review also examines the potential of cubosome-encapsulated verapamil, a calcium channel blocker, as a promising candidate for rapid and effective cluster headache relief. Furthermore, it addresses the challenges and future perspectives in the development and clinical translation of cubosome-based intranasal therapies. By synthesizing current research findings, this review aims to provide insights into the potential of cubosome-based nanocarriers as a transformative approach in the treatment of cluster headaches, paving the way for more effective, patient-friendly therapeutic options.

HNY and right on Jon, exactly - CH is pretty much a stress-test for Helsinki and CIOMS. I can only imagine the complexities of designing CH studies that advance knowledge but always place the well-being of the study participant first, let alone sitting on the ethics committees that have to review and approve them. Check out the below, part 33. World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects https://jamanetwork.com/journals/jama/fullarticle/1760318 And the Council for International Organizations of Medical Sciences, guideline 5. https://www.ncbi.nlm.nih.gov/books/NBK614415/ I saw a few posts on socials in recent weeks venting that there isn't enough research on CH and I get it but I also want to acknowledge that like the lead author of this study, we have some amazing researchers in our corner and I am so thankful for that as well as excited to see what happens in 2026. I feel we saw some real advancement in our understanding in 2025. Thank-you for bringing up this very relevant point.

Thank-you to the researchers. The study was exploratory and only had 18 participants split into three groups so the lack of statistical power is the likely reason for the discrepancy where the single-dose group showed a large effect size against placebo yet the primary outcome for the trial failed to reach statistical significance. And the single dose group reported greater improvement than the two dose group... could be just simply random variability again due to the small sample. Diphenhydramine was used to mimic the effects of psilocybin yet they found it only "partially substituted" for them, do they mean the participants may have been able to distinguish the active from placebo and potentially biased the self-reported headache diary results? i.e. expectation bias. Given the placebo performed unexpectedly well, should we be asking if diphenhydramine has therapeutic potential for migraine? Batch has previously said the neuropeptides involved in migraine and CH such as CGRP, PACAP, SP etc can trigger mast cell degranulation, histamine release and a self-sustaining feedback loop hence the early recommendation to take Benadryl (diphenhydramine) or more recently the full monty supplements with the D3 regimen for CH. Looking forward to larger trials. Welcome to read the study at link above or interact with it in NotebookLM (AI) below. https://notebooklm.google.com/notebook/94236d69-1463-4b24-93a4-a3870f7e9701?authuser=1

Comparing single- and repeat-dose psilocybin with active placebo for migraine prevention in an exploratory randomized controlled clinical trial Emmanuelle A D Schindler, Christopher H Gottschalk, Brian P Pittman, Deepak C D'Souza Published in Headache on December 29, 2025 Link: https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.70024 Abstract: Objective: The goals of this study were to examine the therapeutic effects and safety of psilocybin given as a pulsed regimen for the prevention of migraine and to consider the blinding integrity of an active control agent. Background: The administration of a single low dose of psilocybin was observed to have lasting therapeutic effects in one small pilot trial in migraine, although the ability of a pulse dose regimen, as practiced by patients with cluster headache, to potentially improve magnitude and/or duration of transitional preventive effects has not been studied. Furthermore, comparison to an active placebo agent that adequately mimics the acute subjective effects of psilocybin is required to improve blinding integrity and measure placebo effects. Methods: In an exploratory randomized, double-blind, placebo-controlled, parallel group study, adults with migraine having at least two weekly migraine days at baseline (n = 18) participated in two drug administration sessions separated by 7 days during which they received zero, one, or two doses of psilocybin (10 mg; psi). Whenever participants did not receive psilocybin, they received diphenhydramine (25 mg; diph). Participant recruitment took place between September 2021 and August 2023. The primary outcome measure was a change in migraine frequency using headache diary data collected starting 2 weeks before and continuing through 8 weeks after the second drug session. Results: In the 2 weeks after completion of the two drug administration sessions, the change from baseline in migraine days/week was not significantly different among groups [diph-diph: -0.7 (95% confidence interval, -1.5 to 0.2); diph-psi: -2.0 (-3.0 to -1.0); psi-psi: -1.7 (-4.1 to 0.7); Χ2 (2) = 4.56, p = 0.102], despite large effect sizes against the placebo group in the those receiving one (diph-psi; d = 1.66) or two (psi-psi; d = 0.69) doses of psilocybin. Similar reductions in migraine frequency approximating 50% were seen in all groups over the 8 weeks measured. The difference in 50% response rate among groups over 2 weeks, however, approached significance (diph-diph: 17%; diph-psi: 80%; psi-psi: 80%; p = 0.087). Drug confidence ratings (i.e., blinding integrity) suggested that diphenhydramine partially substituted for the acute effects of psilocybin. No correlations were observed between changes in migraine frequency after psilocybin and drug confidence, acute general drug effects, or acute psychedelic effects. No serious or unexpected adverse events occurred. Conclusion: This exploratory study found similar reductions in migraine frequency with single-dose psilocybin, a two-dose pulse of psilocybin, or diphenhydramine placebo. Whereas blinding was incomplete in this study, this important topic is highlighted in the study design and findings. The potential for psilocybin to serve as a transitional treatment in migraine remains but will require careful planning in future studies to separate drug and non-drug effects. Furthermore, the inclusion of headache specialists in the design and execution of these future studies is necessary to preserve the viability of psilocybin treatment in headache medicine.

As I said in my other post, I’m pleased to have you here - whilst sorry you are in a bout, you have a good vibe that I resonate with. Yes! I have thought more than once about most of your suggestions and I love it - whether there is an out of the box solution or something custom, there is an old world charm about the forums here that I really do appreciate but understand if it was a little more in line with the times like integrated into an app it might be able to add more value, whether support, social connections, helping more people, fellowship etc. Someone from the awesome admin team might be able to give an update on any behind the scenes improvements that are in the pipeline. I’m sure I read somewhere there were some website things in the works. Good on you for offering your skills man, that’s what I just love about this community, people are too good.

Do you guys say this as you slurp another piece of fermented shark from the tin? Hehe. I really love that saying though, I will remember that! Sorry to hear about your bout with pneumonia, glad you are on the mend from that - hopefully the steroids and I suspect antibiotics didn't mess you around too much. A couple of years ago I had a real bad run with a recurrent bacterial infection that used 5 rounds of antibiotics before my doctor presented a biologic which I had said absolutely not in a million years - saw a functional doc, got it under control but low and behold that was the one year I fell from cluster free remission whilst maintaining the target vitamin D3 range - opened my eyes to a few different topics including microbiome - sorry to say I don't know that the fermented shark packs a probiotic punch like kim chi though. You also mentioned in another post about foraging up there in Iceland for medicine, I suspect your varieties would be quite different to what's found in more warmer climates. It's the same in New Zealand, we have mystical magical varieties down under, one example being Psilocybe weraroa, they look like little blue testicles and pack a heck of a punch. Happy to see you here on the forums - I recently landed here earlier in the year, good bunch of folk here and we all seem to love cats. I feel like this is the more appropriate place to share recent research. So... I sign off by saying Happy new year and thank-you for the old one!