Tumor Necrosis Factor

[Ricardo]

It's midnight...I busted a cluster with a decent amount of Ketamine and I'm a little whacked out...I've been planning on posting soon, But I keep itching to share my recent research...This seems like all encompassing information for the masses...The kinda info that can help so many people, cluster suffers and millions of others...The kind of info that shows just a touch of the promises of our magic medicine, but in a way that western medicine has difficulty dismissing...  Maybe I'm getting ahead of myself....

I guess it all started with me talking to a friend the other day...and he starts telling me about the experiences that a guy I know has been having battling Crohn's disease.  He told me he has been taking injections of a nasty drug that he does not like (Remicade), but lately has been taking LSD instead.   LSD for Crohn's?    I was amazed---I tell all sorts of people to take all sorts of stuff but I can't imagine myself recommending hallucinogens for a disease like Crohn's.....

Tumor Necrosis Factor (TNF) was not a term I had ever heard before, but once I started looking into Crohn's and LSD it kept popping up...

From Wikipedia:

The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, to induce apoptotic cell death, to induce sepsis (through IL1 & IL6 production), to induce cachexia, induce inflammation, and to inhibit tumorigenesis and viral replication. Dysregulation of TNF production has been implicated in a variety of human diseases, including Alzheimer's disease,[1] cancer,[2] major depression,[3] and inflammatory bowel disease (IBD).

The more I read about it, the more I hear the words inflammation repeated over and over...(not to mention nitric oxide synthase activity)    And the more I read I keep getting all giddy.  I'm such a brain geek.  But this research is awesome.

This awesome study came to the conclusion that "DOI (http://en.wikipedia.org/wiki/2,5-Dimethoxy-4-iodoamphetamine) Superpotently Inhibits TNF-[ch945]-Induced Expression of Proinflammatory Genes ICAM-1, VCAM-1, and IL-6 in Primary RASM Cells

http://jpet.aspetjournals.org/content/327/2/316.long

This study confirms what I've been reading over and over, that drugs that stimulate or are "agonists" of the 5ht2a receptor do a really awesome job of knocking down the amount of TNF in your body for periods of time that are much longer than the amount of time that the drugs are in your body.  (notice how it says "superpotently inhibits" not just "potently inhibits"....) All of our favorite clusterbuster drugs activate the 5ht2a receptor.

I keep finding more articles to read...I've got a bunch on my list and I'll post them once I've gotten a chance to really read them (ketamine is not the best drug to help info soak in )

For now 2 things stick out to me:

-everything I've read makes me believe this is implicated in our clusters

-The number of diseases that could be getting months of relief from one dose of LSD is completely ridiculous....

-Ricardo

[Ricardo]

And here's a publication explaining how Tumor Necrosis Factor potentiates  glutamate excitotoxicity....Which hints at ideas of why drugs that are NMDA receptor antagonists (drugs like Ketamine that block glutamate excitotoxicity) would work for clusters....For whatever reason (which I am determined to figure out ) I think our TNF is out of control, which is boosting brain glutamate levels to toxic levels, causing our clusters. 

And all the people around me are thinking I've completely lost my shit because I won't stop talking about Tumor Necrosis Factor, 5ht2a receptors, glutamate and awesome drugs that will save all of western medicine from our myriad of inflammation woes....At least I know you guys are listening!

http://www.ncbi.nlm.nih.gov/pubmed/20849956

-Ricardo the TNF talking, 5ht2a receptor freak  ;D

[Ricardo]

Redbull anyone?  It'll suppress your TNF alpha production.....

http://www.ncbi.nlm.nih.gov/pubmed/15313438

[Bonkers]

No offense, please, Ricardo. I'm interested and anxious to learn but my eyes tend to glaze over when I read scientific jargon dominated by foot-long words I've never seen before. Maybe if you dumbed-down your posts, just a little, for people like me, more of us would follow your links.

Ron

[CHfather]

Related to what Ron just said, I've been thinking that maybe if you identified some specific research questions you wanted others to help you with -- even if it's just finding references for you to make sense out of -- probably some of us would be glad to do it.  (Or I would, at least.)

[Ricardo]

No offense, please, Ricardo. I'm interested and anxious to learn but my eyes tend to glaze over when I read scientific jargon dominated by foot-long words I've never seen before.

No offense taken   I can completely understand how this is confusing, I've been pouring over this stuff for almost a week, looking at all sorts of articles trying to make heads and tails of all this info...And I might not always explain things that well when I'm whacked out on Ketamine

The basics are this--There is a substance produced by the human body that has as a major effect inflammation, it's called Tumor Necrosis Factor, but let's just call it TNF.  The amount of TNF in your body is greatly reduced when you activate very specific serotonin receptors (the 5ht2a receptors).  These serotonin receptors are the same ones that get hit hard by all our clusterbusting drugs.  So one result of taking hallucinogens is a lowered amount of TNF in your body, and it sounds like it can do this for a good length of time.  In other words we have found a very inflammatory substance that goes away for months at a time when we take hallucinogens.  No one has been able to say how the hallucinogens have been able to keep peoples clusters away for months at a time, and I theorize that this is the reason.

At this point this is all theory, and I don't know how this is going to help us deal with our clusters today...but I find it fascinating  (if you can't tell )

The only research question that this is bringing up for me, and I would love anyone's input on is---"What factors in the human body cause a rise in TNF levels?"

-Ricardo

[Bonkers]

Now I'm interested. Thanks, Ricardo.

[CHfather]

Ricardo, with the understanding that I know nothing except what I figure out, maybe wrongly, from what I read, here are some thoughts.

I think our TNF is out of control

If I'm reading it right, there's a blood test for TNF levels that's used in many studies.  Would running this test on people with CH help resolve whether your thought here is accurate or not?  (Not saying that you or I or any of us have the capacity to bring about that kind of testing, but as a result of Batch's anti-inflammatory regimen, a lot of people are now insisting on having their vitamin D3 levels tested. No idea what would be involved in requesting a TNF test, whether it's a common thing or a complicated thing.) http://www.dialogues-cvm.org/pdf/17/DCVM17_07.pdf

Note that the study you cite shows that 5ht2a receptors exist outside the brain, and that activation of those outside-the-brain cells also very strongly inhibits production of TNF (I think this is the same study -- the title you gave for it is different):

>>>The G protein-coupled serotonin 5-hydroxytryptamine (5-HT)2A receptor is primarily recognized for its role in brain neurotransmission, where it mediates a wide variety of functions, including certain aspects of cognition. However, there is significant expression of this receptor in peripheral tissues, where its importance is largely unknown. We have now discovered that activation of 5-HT2A receptors in primary aortic smooth muscle cells provides a previously unknown and extremely potent inhibition of tumor necrosis factor (TNF)-[ch945]-mediated inflammation.<<<  http://jpet.aspetjournals.org/content/327/2/316.full.pdf

You would think that TNF blocking drugs, like the one your friend's friend was taking (remicade) would be effective against CH, wouldn't you?  I don't see any studies of that, for any of them (enbrel, humira, cimzia, simponi).  In fact, there are reports of 5 people developing CH within a month of starting remicade: http://www.ehealthme.com/ds/remicade/cluster+headache

Of course, the percent of people reporting CH after starting remicade is about the same as the percentage of people with CH in the general population, so it might be meaningless, but it's interesting to read the symptoms listed by people who report getting headaches from TNF blockers: http://www.medhelp.org/posts/Arthritis/TNF-Blockers-and-Headache----Humira--Enbrel--Remicade--etc/show/324130

If I can say so, the "vitamin D3" anti-inflammatory regimen is also tackling this TNF issue.  D3 and fish oil, the core active elements in that protocol, are both TNF blockers:

>>We found 1alpha,25-(OH)(2)D(3) could significantly suppress TNF-alpha<<: http://www.ncbi.nlm.nih.gov/pubmed/20722932

>>There was a significant inverse exponential relation between TNF alpha or IL-1 beta synthesis and mononuclear cell content of eicosapentaenoic acid (EPA), an n--3 fatty acid derived from ingested EPA (fish oil) or metabolism of ingested alpha-linolenic acid (flaxseed oil).<< http://www.ajcn.org/content/63/1/116.short

I realize that your excitement is more related to the potential general healing powers of psychedelics.  Just offering all this in case it leads you anywhere worthwhile.

As for your actual question -- >>The only research question that this is bringing up for me, and I would love anyone's input on is, "What factors in the human body cause a rise in TNF levels?"<< -- the only answers I have for now are either useless -- it's plainly in many cases a genetic predisposition -- or essentially circular -- things that cause inflammation (by activating, or "degranulating," mast cells) raise TNF levels, and increasing TNF levels cause further increases in TNF levels. >>Activated mast cells are source of inflammation. Large amounts of TNF-[ch945] are quickly released by stimulated mast cells. All the cells involved in inflammation have receptors for TNF-[ch945] and are activated by it to synthesize more on their own. This positive feedback quickly amplifies the response.<< http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/I/Inflammation.html#Tumor_Necrosis_Factor-alpha_%28TNF-a%29

>>Mast cells can be stimulated to degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics such as polymyxins]), cross-linking of Immunoglobulin E (IgE) receptors, or by activated complement proteins.<<  http://en.wikipedia.org/wiki/Mast_cell

[Brew]

I take a bi-weekly injection of a drug designed to suppress my body's overproduction of TNF. It's called Enbrel. It was originally designed to treat rheumatoid arthritis, but has also gained favor amongst dermatologists for treating certain types of psoriasis.

The condition I'm being treated for is called Hidradenitis Suppurativa. Mine is an off-label use. The symptoms are chronic, large, infected cysts and abscesses. Mine are in the perineal area, but others get them on the scalp, back of the neck, under the breasts, and in the armpits. When it's chronic, like it has been for me since my teenage years, life can be one huge pain in the ass, all the time.

Use of this TNF-suppressing biologic drug has reduced the duration and intensity of the boils I get by about 75%. It's expensive, but it has made as much impact on my quality of life as busting has.

[Bonkers]

Yo, CHf

Howz about we swap brains? I'll even toss in a few bucks. . .  plus my dog.

Come on, whadaya say?

Ron

[Ricardo]

You would think that TNF blocking drugs, like the one your friend's friend was taking (remicade) would be effective against CH, wouldn't you? 

That's the thing that throws off my whole theory of TNF being implicated in clusters...I haven't found anyone who has gone on TNF inhibitors and reduced their clusters, while I have found the same thing you did CHF--people mentioning getting hit after starting the TNF inhibitors.  I think this could mean a couple different things...either

1.  Clusters and TNF have nothing to do with each other

2.  TNF lowering drugs like Remicaide really suck for clusters....Kinda like how NMDA receptor antagonist seem to work well for clusters, but not ALL of them---Alcohol is an NMDA receptor antagonist, but it sure doesn't help for a cluster

I'm sure there is a third, fourth and fifth option that I can't think of, and would love to hear anybody's ideas.

I have to admit a lot of my excitement about this comes from all the non-cluster disorders that can be helped by this.  My idea that TNF and clusters are connected are definitely just my theory that is quite rough around the edges.  But there are numerous health problems that have been proven to get better when you lower high TNF levels, and according to all this research, taking hallucinogens should help...At one point as humans we ingested these types of substances at least a couple times a year, for the solstice....Sounds like a huge dose of anti-inflammatory, anti-depressant action for the masses and I wouldn't be surprised if a lot of western medicines autoimmune and inflammation problems would be greatly reduced if we picked up our old habits again....(Good Luck )

Another excitement aspect of it really has to do with getting Bol-148 on the market.  My friend is all psyched because he thinks that Bol-148 is going to be able to help his Crohn's...And theoretically it should.  Theoretically (I'm pretty sure on this, but not POSITIVE that Bol-148 hits the same serotonin receptor, the 5ht2a receptor--anybody have any info on that?) Bol-148 should be able to help Alzheimers, cancer, psoriasis, and a host of other inflammation and TNF related diseases....I remember someone talking about how much easier it would be to get this stuff on the market if we could prove it is beneficial with migraines--this would be ten fold that

I take a bi-weekly injection of a drug designed to suppress my body's overproduction of TNF.

Brew-

Have you ever noticed differences in the H.S. after busting?  Do you know much about gettiing a TNF level test, is it just a simple blood test?  It would be interesting (if your doc is on board) to see the differences in the TNF levels if you got a test done before and after busting (don't feel obligated to be our lab rat though  )

Happy New Years Folks, I think it's gonna be a good one [smiley=evil.gif] [smiley=evil.gif] [smiley=evil.gif]

Ricardo

[Brew]

I've never had a TNF level measured, but I'll ask next time. He might consider it pointless since I have no baseline, but he wouldn't be put off by the busting question (he's a long ponytail kinda guy).

[CHfather]

>>>

Theoretically (I'm pretty sure on this, but not POSITIVE that Bol-148 hits the same serotonin receptor, the 5ht2a receptor--anybody have any info on that?)

  Ricardo, this is all way too complicated for me, but here's a passage from the 2010 article about BOL by Halpern and others.  I might be taking it out of context . . . but I'll leave it up to you to do the heavy lifting.

>>>However, prolonged administration

of BOL-148 does not result in cross-tolerance

to LSD (15). This, in turn, suggests that BOL-148Â’s

mechanism of action for CH is unrelated to those

receptor systems thought to be involved with hallucinogenicity:

5-HT-1A and 5-HT-2A.  The ergotamines (including BOL-

148, LSD, dihyroergotamine, and methysergide) likely

have positive treatment effects for CH through serotonin-

receptor-mediated vasoconstriction.<<< 

Bottom of p2 at http://clusterheadacheinfo.wdfiles.com/local--files/file%3Abol-148/BOL-148.pdf

Sewell makes what seems to me to be an interesting, possibly related, point in a 2010 discussion about BOL. >>We don't have any particular reason to suppose that LSD's effects on headache are mediated by 5-HT2A; it affects a lot of receptors.<<  Again, I don't know enough to know if this is important to your thinking or not, but it seems related to what you're asking.  It's here: http://www.dosenation.com/listing.php?id=7955

[Ricardo]

Ricardo, this is all way too complicated for me, but here's a passage from the 2010 article about BOL by Halpern and others.

My take on this is that the authors of the article are saying that they assume BOL does not hit the same serotonin receptors LSD does, because it does not cause hallucinogen like effects. BUT...this is based on the assumption that LSD makes you hallucinate by hitting these serotonin receptors (5ht2a receptors) AND that assumption is all wrong.

   This is what Dr. Sewell is pointing out, that just because LSD hits these serotonin receptors, that does not mean that hitting these receptors is the CAUSE of the hallucinogenic activity.  Or in other words, LSD does lots of stuff, one small part of it is hitting the serotonin receptors--but there's a hell of a lot more going on than just that.

The idea that hallucinogenic activity is caused by hitting the 5ht2a serotonin receptors has been around for a while, but has been challenged by many people.  From everything I have read, I do not believe at all that hitting this serotonin receptor is what causes hallucinogenic activity--I will try and find the links to a paper Sasha Shulgin wrote where he lists a bunch of drugs that hit the 5ht2a receptor, but do not cause any sort of hallucinogenic activity.   I would post a link to a ridiculously hard to interpret paper I just found listing all sorts of hallucinogens and what receptors they hit, but it's an amazing enough article that I think it might just deserve it's own link.

To sum it up in relation to TNF....It looks like no one knows, not even Halpern, if Bol-148 hits the 5ht2a receptors.  I hope it does, and so does my friend---but if not, I guess we'll just keep eating acid

-Ricardo

[Bonkers]

It appears to me, just from the responses of those who post on this website, that the efficacy of LSD in aborting/preventing CH depends on at least having a mild hallucinogenic experience. Ingesting a lesser amount just doesn't seem to have any effect on CH. It doesn't appear that anyone can really say, with any authority, which receptors - if any - I mean, the actual mechanism by which LSD/BOL effects CH - nobody knows. BOL is ingested in milligram amounts vs LSD in micrograms - that's thousands of times more, and it doesn't make you trip. So, obviously, the psychedelic experience itself has no relation to CH. Tripping doesn't effect CH, though all the psychedelics, in varying amounts work to prevent/abort the CH hit. I don't think anybody has any idea really either in regards to the genesis of CH or to it's demise in human subjects. We just know that this class of chemicals works. The how and the where and the why - I think it's all guesswork.

Ron

p.s. - I know I'm gonna get hit on this. That's okay. Many of you know far more than I do re this subject. This post is intended to provoke a learning experience for me.

[FunGuy]

Do you need to have a hallucinogenic experience to bust a CH, or not?

I've heard from knowledgeable Docs with opinions on both sides of this topic, it makes for fascinating conversation until their talk gets beyond my understanding.  :-)

Sub-hallucinogenic, no hallucinations or full trip?? 

My opinion is that a successful bust is not dependent on having or experiencing a trip,  but for some (including myself) to reach a therapeutic dose of psilo or lsd a trip is going to happen.  I believe its not the trip, but the amount.  (Bob said that once, lol)

For comparison, it's kinda like taking a Tylenol for a tension headache.  Some people get away with 500 mg and some need 1000 mg.  It may not depend on size, body weight or intensity of that headache, some people just need more.   tolerance, adaptation, secondary factor.  Who knows??

As for how this class of chemical works, the truth is there is so little know about most medications.  Efficacy is based on results and while they try to understand the physical and physiological pathway that often is not know.

Using Tylenol again, read how it works:

http://www.rxlist.com/tylenol-drug/clinical-pharmacology.htm

"Although the exact site and mechanism of analgesic action is not clearly defined........"

Some day I'm sure we will know how all this stuff works, tylenol, psilo, lsd and TNF.

Hopefully by then CH will be eliminated also.

Thread like this may lead to that!!

Sorry, not trying to sidetrack the thread, this is all fascinating.

And yes, most of it is way over my head too.

FG

[Purple]

bumping this, hoping to get a few of us back into searching more answers about 5HT2a receptor, other receptors, dopamine, melatonin, TNF...

After many readings and research about serotonin (5HT) receptors, LSD, and so on, my feeling was that the actions of LSD, and probably psilocibin, are probably far more complicated than what I first tought and are mostly unknown. Ever since I was a member here (Jan 2012), I have been under the impression that the main action of psychedelics on clusters was through the 5HT2A receptor, but obviously, this is more than unsure.

I am surprised also to find out that the action of sumatriptan (Imitrex) on clusters and migraines is actually also unknown to science, and that many other prescription meds mechanisms of action is also unknown (even Tylenol ). They know sumatriptan mostly hits the 5HT1B and 5HT1D receptors (or am I mistaking here?), but they have no idea what that does exactly, and they suppose that vasoconstriction... Wikipedia: "Sumatriptan is also shown to decrease the activity of the trigeminal nerve, which, it is presumed, accounts for sumatriptan's efficacy in treating cluster headaches."

The ordinary citizens nowadays live their lives thinking that science has many answers, that consulting a doctor or a specialist will lead to clear answers. When one gets a little further into this, he/she finds out that... there are no clear answers. "Medecine is not a science, it's an art", as my friend says. Try this and come see me again, we'll adjust... That sounds a bit like the kid poking a toad with a stick story. Freaky...

I don't remember the thread, but I remember reading here that we clusterheads can rely better on ourselves than on any (science) machine to get answers since we are the machine.

About this, I find particular that I have a hard time today, as my cycle is fading out, getting intellectual enough to absorb all this scientific information, whereas when it is impossible for me to sleep for days and very high on my cycle, I eat and absorb this information like candies, and even go further (or at least think that I go further in thinking). My brain seems flat today, and when cluster attacks hit one after the other, my brain seem to be hyperactive and able to go beyond my actual intellectual capacities.

After analysing myself through this cycle, I find that the circadian rythms are probably the most important thing associated with clusters. My readings thaught me that not only the hypothalamus regulates the circadian rythms.

Well OK, I knew that already, most here do. But after this cycle, studying myself and reading get me to think that it's more important than we thought, and that sleeping and dreaming might be more closely linked than... well than I thought. I was seing my circadian rythms' absolute mix up as a symptom of my cluster attacks, and now I'm starting to see it as a direct cause... well maybe.

As for Tumor Necrosis factor, I saw on the other board that Ricardo posted recently (or was that an old post I have read, Ricardo?) about this, as he still thinks it's closely related to clusters.

Is it because my cycle is fading away? I can't seem to quite understand what it all implies.

Ricardo, if you would post more information on TNF, more of your thoughts on this, it would be a pleasure to read it.

But I think if TNF is a factor in clusters, it cannot be the only one. There are so many twisted things in my body, feelings, head, off cycle and in cycle, and some of these seem so different from other clusterheads', that it's difficult for me to think there could be only one thing that leads to clusters.

If, as mentioned earlier in this thread here, tripping would be necessary to treat the clusters, how then could BOLD-148 work... and the RC seeds... they work very well to bust, and I couldn't get much of a trip out of these even with high doses.

And if too much TNF leads to clusters, why is it that meds that reduce TNF doesn't help for clusters?

It seemed obvious for me at first (becoming a member here) that playing with the serotonin system, hitting the 5HT2A receptor, was how the busting agents worked on clusters. Now it seems to me no one knows much of anything on anything...

and that maybe it's actually not science that can help us.

:-/ :-/

[Ricardo]

I've been wanting to post on this for a while, thanks for spurring me on.  I will throw out the research that I have done and ideas that I have come up with, later I will try and find some links.  (today is too nice of a Saturday to spend inside on the computer )

First off, damn close to every cluster drug I have investigated lowers TNF levels.  Seriously.  The ones that work on clusters but have always seemed weird because they are blood pressure meds (verapamil) or mood stabilizers (lithum) to caffeine, to ketamine, to psychedelics, to Imitrex, they are ALL TNF inhibitors---enough so that there are pub med articles detailing these actions in these drugs.  I found one article specifically stating that the researcher was thinking that Imitrex may be working by lowering TNF levels.

I think that this is one more key in understanding clusters, but it is not a big huge breakthrough in Cluster science...The reason I say this is I think I found the relationship between TNF and clusters.  High levels of TNF increase the Nitric Oxide pathway, a well known trigger for clusters.  IF you have high TNF levels and are prone to cluster headaches you will end up with a cluster.  Maybe this is what chronic CH is really all about.  A person genetically predisposed to Clusters, who ends up having their TNF levels rise out of control and constantly increasing the Nitric Oxide pathway just ends up having the constant cluster that won't go away.

My guess is that high TNF levels are not the only thing increasing this Nitric Oxide pathway, just one.  And then it starts to make sense as to why so many people have so many different reactions to various meds.  Verapamil works for some, but not all.  Same with Lithium, Seems like the same with all sorts of drugs. 

The psychedelics seem to me (although we have no real studies showing this) to be the most all encompassing therapy.  From the responses that people put on this board it makes me think they have a better success rate than just about everything else...But again, no hard data to prove that.

My bet is that the psychedelics are giving a one-two punch (or maybe a 1,2,3,4,5 and 6 punch )  As in, I think there is more than one mode of action happening here.  I think the TNF levels getting lowered helps a lot of people (This may in fact be why the Psilocybin is such a good abortive for me) but I also think the direct action on the 5ht2a serotonin receptor is doing some unknown action that is stopping many peoples clusters for months at a time.  I would not be surprised if as we investigated more and more, we find that the psychedelics hit numerous buttons in the brain and body that are beneficial for cluster headache sufferers.

As far as

why is it that meds that reduce TNF doesn't help for clusters?

I think that the relationship between TNF inhibitors and cluster headaches has not really been investigated to say whether western Medicines TNF inhibitors would be any help.  It could be that we need to get the RIGHT TNF inhibitors.  As in, there may be TNF inhibitors that have side effects that actually end up negating the positive effects of TNF inhibition.  A very loose example of this type of situation would be with the NMDA receptor antagonists, which have been helpful for many cluster suffers as these include Ketamine and Nitrous Oxide--but the class of NMDA receptor antagonists ALSO includes alcohol, which will never help your clusters because they stimulate that Nitric Oxide pathway a bit too much.

All this info is great, but it leads me to the real question--IF high levels of TNF are a problem here, why do we have such high levels of TNF in the first place?  Tumor Necrosis Factor does exactly what it sounds like, Necrotizes (eats away) tumors.  In many cases it rises when a person has cancer, to fight off the tumor.  (Don't get scared folks, we do NOT all have undiagnosed cancer)  After some reading though, I found TNF levels also rise in response to viruses.   Could we be suffering from undiagnosed, and undetectable viruses?  Correct me if I am wrong, but I think you can only test for a virus that you know about....And if I am also remembering right I think that a while back there was a cluster researcher that got laughed at pretty hard because he was saying he thought there may be a virus component to Cluster Headaches. 

All of this is complete theory, and I don't buy it all 100%...But it is interesting to say the least.  I'm going to keep at this, especially when I bust.  It seems like the times that the most important, significant ideas come to me when I am in that deep mushroom trance.... I feel like I am completely out of my body and in a sea of information that I dreamily catch and grab like plucking a ripe apple from a tree. 

Not sure if tonight is one of those nights, but soon...

-Ricardo 

[Bejeeber]

That's some brilliant information plucking Ricardo. Thank you.  8-)

[Purple]

Am I ever glad I bumped this thread, and thank you Ricardo for elaborating more on the subject of TNF.

I must admit that after a few hours of reflexions and readings on TNF, I ended up listing many reasons why your theory wouldn't fit clusters. How could it explain things like confused circardian rythms, cycles starting at equinoxes or solstices, barometric pressure sensibility, low levels of testosterone and vitamin D, the fact that we get hit after one hour of sleep, and not if we stay awake, the fact that most clusterheads have poor hunger...

And how could it explain the fact that this scan study shows clearly that the hypothalamus has abnormal activity while a cluster is taking place, and between attacks during a cycle? http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057896

I was about to turn away from TNF having any link with clusters for it seemed clear to me that a hypothalamus misfunction HAS to be the main reason for clusters...

So I thought: the only way TNF could be linked to clusters is if TNF is linked to a possible malfunctioning of the hypothalamus.

And it is !! or at least it seems to be. The following links provide little direct answers to my questions, but... I think the link is there (between TNF and hypothalamus, at least for the hunger part)

Now I'm not sure the following links are all totally relevant, and of course I didn't read them thoroughly, but I'm quite certain it brings some water to the mill

http://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha

It has a number of actions on various organ systems, generally together with IL-1 and Interleukin-6 (IL-6):

    On the hypothalamus:

        Stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH)

        Suppressing appetite

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2006.03857.x/pdf

In addition, TNF-a induces the expression of neurotransmitters involved in the control of feeding and thermogenesis. Thus, TNF-a may act directly in the hypothalamus inducing a pro-inflammatory response and the modulation of expression of neurotransmitters involved in energy homeostasis.

http://www.ncbi.nlm.nih.gov/pubmed/20576518

The icv infusion of TNF-alpha-induced an increase in PTP1B protein expression and activity, and attenuated insulin and leptin sensitivity and signaling in the hypothalamus.

http://www.ncbi.nlm.nih.gov/pubmed/17459524

In conclusion, TNF-alpha, on a dose-dependent way, modulates insulin and leptin signaling and action in the hypothalamus.

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2006.03857.x/pdf

In conclusion, this study shows that TNF-a can activate a

cascade of signal transduction in the hypothalamus of rats.

These signaling events induce the expression of cytokines

and other proteins related to inflammatory signaling that, on

a long-term basis, may have implications in the local

response to a pro-inflammatory stimulus.

http://www.jimmunol.org/content/155/7/3552.abstract

http://qjmed.oxfordjournals.org/content/93/6/323.long

This is very complicated studies; I spent the whole Saturday reading and I'm not yet reaching any conclusion, but I now really feel you struck a goldmine here, Ricardo (couldn't find the right translation for my image).

Now why we would produce too much TNF is another story... I guess, yes, an unknown virus could be the cause, and why do episodic have cycles, and are not hit constantly is another question, but that could be related to the way the virus functions (may function as the herpes virus that comes and go?)... And how would busting be related to this... I have read that LSD seems to be a powerful antioxydant, who knows what else it does, and what exactly does hitting the 5HT2A receptor do? I think this is still quite obscure, but it all sounds promising.

Anyways, this is jungle so far, but I think there could be a gold mine underneath if we clear the bushes a little.

and I'm sorry in advance if I posted this without first digesting it all. I guess I meant to stimulate anyone else's curiosity and bring them to dig for more info 

[Ricardo]

I must admit that after a few hours of reflexions and readings on TNF, I ended up listing many reasons why your theory wouldn't fit clusters. How could it explain things like confused circardian rythms, cycles starting at equinoxes or solstices, barometric pressure sensibility, low levels of testosterone and vitamin D, the fact that we get hit after one hour of sleep, and not if we stay awake, the fact that most clusterheads have poor hunger...

I agree with all of this (or I did until you posted that awesome info about the hypothalamus TNF connection--that's some really crazy info that I had never come across....Good Find!   but one thing at a time )    The idea that I have had was that High TNF levels and cluster are completely separate things, but unfortunately (because essentially some people have bad genetic luck) some folks have both cluster headaches and high TNF levels, leading to Chronic CH.   The info that you posted is making wonder if there may be more to it than that. 

Again-- GOOD FIND!

I do not have time to really check out those links in depth right now, but I will.

-Ricardo

BTW- one other TNF thing I neglected to point out...High amounts of Vitamin D are also known to lower TNF levels.  Batch's remedy may be doing different things than we have all hypothesized....I know I found a specific study showing that Vitamin D lowered TNF levels in humans, but NOT until you reached pretty high amounts, right around the dosage a lot of Clusterheads seem to get relief.  I'll look for it.

http://www.sciencedaily.com/releases/2012/02/120223103920.htm

[didgens]

So has anyone tried ENBREL for CH?

[Brew]

So has anyone tried ENBREL for CH? 

I have been on Enbrel twice per week for three years until just a couple of months ago for a different condition (described above), and I can tell you unequivocally that it had no effect on my CH whatsoever.

Recently my doc put me on Humira because Enbrel started to lose its effectiveness in treating my HS. Mine cannot be considered anywhere close to a controlled study because I started the high dosage vitamin D3 regimen in March of 2012, and I have been completely pain-free from a CH standpoint since May, 2012. I continue to take 10,000iu of D3 along with the other minerals and fish oil daily (not going to mess with a good thing).

The HS is suppressed rather well with the Humira, but I don't know if the Humira is having any effect on keeping my CH at bay.

[didgens]

thanks brew

[spiny]

So, if we have high TNF, is that why, even as heavy smokers, surveys show very few cases of cancer? Seems I read here a long time ago that cancer rates among CH'ers that smoked were somewhere in the .3% category.

Another thought: Would this virus idea be the reason that my WBC is always elevated? Not real high, but always out of normal range on the high side? Docs never have an answer when I question it, just shrug and say 'Don't worry'.

Just thinking out loud.