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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!

So true Jeeb. Unfortunately full and continuous cessation has yet to be achieved through the D3 regimen. Less frequent attacks, regular cycles and intensity of attacks has been greatfully experience from many on the regimen making it a very useful tool for any CH sufferes toolbox.

"Completely CH free" isn't what everyone on the D3 regimen achieves, but glad you've arrived there!

Not sure why but it's definitely sad that it's not a common "go to" treatment. My first thought is that CH is pretty uncommon in itself so that could play a role. Then you have the very much so common migraine that the D3 protocol works for as well which makes my second though lean toward the fact that you generally cant patent naturally occurring vitamins or minerals so there is no reason (monetary) benefit for pharmaceutical companies to bother with it. Tens of billions of dollars are spent annually on migraine medications and unfortunately there are financial incentives for Doctors to influence medication prescribing.

Hi, I was diagnosed with cluster headaches almost 9 years ago and you can go back and read my posts from that time to see my journey. I was introduced to the D3 Protocol/Regimen by CH Father (God Bless You!) at the time. This protocol has genuinely saved my life. I've been CH free ever since I started it. But I recently met someone who's wife had CH and he told me that they had tried everything, I told them about the D3 Regimen and they had never heard of it. I tried looking up treatment for CH online and change my phrasing to get different results but I didn't see the D3 Regimen anywhere. It breaks my heart to know that this life changing treatment where all you have to do is take a bunch of inexpensive supplements to be completely CH free is not common knowledge. I was lucky enough to be guided in the right direction almost a decade ago, but I expected this treatment to be widespread by now, why is that not the case?

It's been four years and I wanted to update my log again. I have been almost entirely headache free (not just CH!) all this time. The only 2 instances where I experienced a mild CH was when I had dropped my dosage of D3 just to see what would happen. I increased the dosage again and haven't had any problems. I should mention that I'm taking 40,000 IU of D3 daily. I sometimes do a 36 hour fast and on my fasted day I don't take any supplements, but my inflammation levels are at their lowest during my fasts so I don't need them anyway.

@Craigo thanks to your recent YouTube video, I think my triggers right now are actually coming from my tooth. It seems the seal of my crown has failed, and sometimes there is pain there (same side as my cluster attack) and could be the trigger for this cluster period. Getting it checked out on Wednesday. Thanks for all the advice guys

Hello, has anyone here tried to treat a cluster with Pantoprazole? After a long time, I had clusters for 7 days and successfully stopped them again with pantoprazole

Ah ok, here’s hoping it yields good results!

It's lower than many might use yes, they are trying a lower dose that would not induce a trip and it's taken every 3 days.

This is great! Hopefully more places follow on. Question though… is 25ug a little lower than the usual busting dose for Vit L?

to add to the great post and info. sometimes the d3 protocol doesn't fully eliminate the hits but it shortens the duration and intensity. have you noticed any of the 2 happening?

Thanks for much for the response, I will try buying a couple more of the supplements you recommended. I'm trying my hardest to not have to use medication to solve the problem. Luckily my cycle should be over in about 2 weeks if things are as consistent as usual (1 month cycle). @Craigo Regards, Darryl

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.

Have u tryed emgality? I get my cluster seasonal so when I do I used to do verapamil and oxygen but now I get my loading dose of emgality and it completely stops my cluster and I dont get them again for another year

When i start getting my clusters i start on emgality and it completly gdts rid of my cycle till the next year around the time the weather changes and i start to get them again, than i just get another emgality shot and im back to normal

Hello everyone, I've been having cluster headaches for about 2 weeks and have been following most of the advice here. Trying to stick to a low histamine diet and increased my vitamin d intake. For some back story, my typical diet consists of high histamines (avocados, bananas, kefir, and reheating left over foods). I have gotten rid of all of these at the moment during this period of attacks I just got my lab results done yesterday and my vitamin D was pretty high yet I'm still getting headaches. What else should I be doing? Right now I take vitamin C, methylated folate, fish oil, magnesium glycinate, zinc, glycine, curcumin, multi vitamin, vitamin D (around 20-30000 IU), vitamin k2, and just recently got boron Thanks for any help @xxx

I initially thought the same, but I was wrong, very wrong with my attempt to supplement estrogen. As with you, soon after starting I was under attack. I added progesterone into the mix but no improvement. As I had mentioned in my previous post, zero attacks during pregnancy for me. I even once said I might just stay pregnant forever so that I don't have Headache but life didnt play out that way. During pregnancy there are 6 main hormones in play. Estrogen, progesterone and prolactin increase and stay at higher levels until birth, hcg increases then slowly decreases, oxytocin jumps in at the end, but relaxin jumps up then levels out and gradually reduces again until birth. Now relaxin relaxes blood vessels to increase blood flow. Relaxin also increases prior to menstation to start preparing the uterus for pregnancy. Relaxin kicks in about day 14 and peaks at day 21, then drops down quickly. Now interestingly, my HA cycle always started day 22-23 and lasted two weeks which coincidentally lines up with the increase and decrease in relaxin hormone.. might be onto something here

And that was a goodie.. Post attack eye attached

Hi, I've had PH for 38 years, I've lost count of how many times I've requested oxygen. It is always denied. Up until about 3 or so years ago, there were clear pain free periods between attacks and between cycles. Now I have constant pain, always around a 2-3 level between attacks with attacks several times a day (sporadic) anything from 6-10 level and now there is no cycles, it's all the time. Example today, 1am woken with level 6, took naproxen lasted 20 minutes, went back to sleep, woken again at 3am with a 7 lasted 20 minutes, woke at 5am with another 7, took naproxen lasted about 30 minutes then no point going back to sleep as alarm went off to get up for work at 5.30am. Got to work at 7am, 8am, level 8, off to hide in the bathroom, for 15 minutes, had tried to ride it out at my desk but couldn't. 11.30am another 8, 2pm, another 7, got home at 4.30pm, 5pm rolls around and hit with a 9, more naproxen, ice pack out, off to hide in my bedroom. All the while I have a lingering low level pain between attacks. Today is the worst I've been in a while. Going to hit the indomethicin tonight at bed time. Have had verapamil in the past, did nothing. Very difficult to get anything here in New Zealand. I was misdiagnosed with CH in my teens, was only a few years back of doing my own research that I heard about indo and managed to convince my doctor to let me try it, it worked and from there rediagnosed with PH. Episodic PH has become chronic HC I'd rather try natural solutions, all these medications just make me feel rubbish on top of headaches. I like to be able to function. I've had some success with keto in the past. I only started keto again on 1st January so I'm wondering if this rough patch is just my body working out what I'm doing to it and it will settle down after a course of indo I did have a bit of a carb binge over the Christmas period so that won't have helped. 7pm and another coming on now, off to get ice and go hide out.

@Nikkk I'll echo Craigs kudos for offering your time and skills!! I've lived long enough to become the elder statesman of the forum having been here since our go live date 16 years ago and counting!! That was Oct of 2009 and at that time the only online support sites were OUCH, clusterheadaches dot com which i think DJ launched in 1998.....and DJ was instrumental on getting us online as a yabb powered sister site. Although I've become the senior member, the jeebster AKA @Bejeeber and @CHfather got here in short order! I think Im safe in saying for all 3 of us that those years of the forum before Facebook were vastly different than they are today!! I've made several appeals at past conferences for folks that I personally know and who were once active members to take a little time and comeback and be a part of this community to no avail!! Although we transitioned to the current forum software probably 10 years ago, it is still a "static" type of board vs the "dynamics" of Facebook. As a result the forum has become just a few active members who support the few clusterheads who happen to find us before they find the many support groups on the "Book"! I was able to have a conversation with our fearless leader Bob at our Conference in Dallas this past September regarding the future of the forum.......I walked away from that conversation not anticipating any upgrades!! However, I can't speak for Bob and will definitely bring this thread to his attention!! The real tragedy is that this is the only place that you get reliable, time proven advice on the "clusterbusters protocol" while in the Facebook groups the term "busting" has become so bastardized that the information and advice is often worthless!! I used to keep my eye on those groups but eventually got tired of sounding like a broken record as I tried to offer correct information when I saw bullshit advice being given and finally just gave up posting there!! As to an app, although I've never used one, I know that there are several out there in use......in fact we had a member here several years ago that developed an app called "Nobism" if I'm remembering correctly......but I haven't heard anything about it either here or Facebook in at least a couple years! Once again, kudos and welcome to the community!!