Over the next two messages I will describe an hipothesis developed over the years and whose application has given me good results.

I apologize in advance in first place by the length of messages, is a work of years that I have summarized as much as possible. I also want to apologize to those who think it is a presumption on my part to publish it, please understand, it's my way of combating CH.

Nor do I intend to give advice to anyone, only check if possible my scenario with other ideas and experiences. Just that.

Finally say that the translation is half automatic, half of mine, so I feel that it must be awful.

Thank you.

Lectures on the cluster headache

Foreword

The aim of this paper is to present a working hypothesis which seeks to explain the phenomenon of CR in every sense, with the sole idea of establishing mechanisms to combat this disease. The greater or lesser success of these methods can be applied directly to determine the reliability of the assumptions.
As the author of this hypothesis is not anywhere near the knowledge or minimum qualifications required for membership of a document of this nature, it should be interpreted merely as a fun “pseudo-scientific document" and all events in the discharge must be considered under this perspective.

The facts and statements that are incorporated in this document are the result of years of careful reading of studies of many kinds. There is no documentation of the sources of such information or its reliability, have just been collected over the years in memory of the author, so absolutely no valid documents. However I urge the reader to accept without more generously in a first reading to get an overview of the working hypothesis, which is what matters, leaving for a second phase, the questioning of the information contained herein.

While seemingly existing documentation on the cluster headache is very extensive, in fact most of it is recurring. Known and classified the disease for decades, most reports are nothing but collections or synthesis of other existing reports. Most of the information in this text comes from psychiatric studies, particularly relating to anxiety, depression or stress, general studies on migraine with fibromyalgia syndrome or Dawn, and even issues such pilgrims as breeding animals or the study of their migration.

Mechanism of the crisis

Before we can hypothesize about the cause of the CR, we must discuss the mechanism by which the characteristic "crisis" or "attacks" of pain occur.

In general, there is a growing consensus that crises are essentially in the inflammation of the trigeminal nerve due to pressure of the cerebral arteries dilated on the nerve. The inflamed nerve contribute to the flow of blood, through the walls of an artery, with a substance called CGRP peptide (calcitonin gen-related peptide), and this peptide and other activate platelets and mast cells, producing a discharge of serotonin and histamine, vasodilator, which would maintain the status of vasodilatation of the artery with consequent compression of the nerve, thus creating a feedback system during the crisis.
There are many other theories, including the question of whether it is before, the chicken or the egg, that is, if the nerve is inflamed for other reasons who initiates vasodilation, or whether, by contrast, is really the first vasodilatation phenomenon and inflammation resulting from it. Raised here because by accepting the first hypothesis that this  may be the real mechanism of the crisis, and we began to build the global scenario. We will also accept, as we shall see below, which need not have such a disquisition of the chicken and the egg, the two concepts are not mutually exclusive.

Also we accept the idea as a second hypothesis, as expressed by the creators of sumatriptan, that vasodilatation is caused by the momentary lack of adequate levels of serotonin, which would be responsible for acting on 5HT1D receptors in the walls of the cerebral arteries, responsible for vasoconstriction. Sumatriptan was in fact designed as a selective agonist of serotonin, that means, serving as it, specifically acting on these receptors to produce vasoconstriction, which should have been produced by at least absent or inadequate serotonin.

Because of the CR

Either way, it is clear that the trigeminal nerve becomes inflamed in many circumstances in CR patients and not in a healthy individual. One might imagine that the neurochemical systems that regulate vasoconstriction and / or vasodilation of the cranial arteries operate incorrectly in CR patients, or, in other words, the CR patients suffering from excessive vasodilatation and that this would be the cause of the problem.

However, it is public knowledge that a patient may suffer a CR of a sudden crisis, or even start a cycle, by a direct action on the trigeminal nerve or its branches. Examples include oral infections, extractions mouth parts, the mere application of a pre-anesthesia tronculares manipulation, otitis and even trauma. If a direct action on the trigeminal nerve can cause a crisis immediately, without any intervention by neurochemical processes, we must conclude that the trigeminal nerve is damaged in some way.

Strengthens our hypothesis the sidedness of the event. If the processes were strictly neurochemical it would be difficult to explain that it only affects one side, and always the same. However, the consideration of physiological sensitivity of the nerve can explain this fact with absolute ease. We do not have the two sides never equal, there will always be a trigeminal more sensitive than the other and it will be the first to be inflamed.

The determination of whether damage is due to friction with the bone structure, damage or sensitivity of the neurons themselves, or any other cause, is outside of this dissertation. It would therefore be the primary cause of CR in this scenario: a particular sensitivity of the trigeminal nerve.

A sensitive trigeminal would ease to ignite at a vasodilatation bit severe, and even normal, in any case depending on the degree of sensitivity of the nerve and the intensity of the vasodilation. These two parameters are those that determine the method and level of suffering of each individual disease: being the sensitivity different for each individual, and although it may also theorized about the possibility of a sensitivity fall, it’s a stable parameter. By contrast, serotonin levels necessary to achieve a vasoconstriction that does not lead to inflammation are much more variable, and therefore, patients in CR are fully exposed and directly dependent on the levels of this neurotransmitter.

The facts explained on the basis of the hypothesis

We’ll begin to use our hypotheses to explain each of the facts relating to the CR.

One-Sided

From the hypothesis we can now easily explain why the disease manifests itself on one side, usually in the same, why the existence of changed hand and their rarity, and even the obvious that persons subject to unilateral surgery begin to suffer the crisis on the other side.

As we have said in passing, and will discuss later, when an inflammation of one of the two trigeminal begins, there is a release of serotonin from platelets. The released serotonin, which will finally end the crisis by vasoconstriction, reverses from the first moment the drop in the level and prevents the other nerve to be affected. This explains in a simple way the one-sidedness of the CR, although in theory there could be some cases, very unlikely, in which inflammation began almost exactly at the same time on both sides, then it would result in a bilateral crisis.

Neither holds any mystery in this scenario the fact of changing the side of the crisis. Some people may have similar sensitivity to both nerves and could ignite one or other without distinction, although it would not be normal. This group is small because it is a coincidence as the two eyes have the same height, just like seeing or hearing same level from both sides, or have both hands identical.

We explain that even within this already small group of people with similar sensitivity on both sides, as is normal that once a cycle on one side, stay there, and just because he has already undergone trigeminal daily sessions compression and inflammation is more sensitive and more likely to be the first to catch fire again.

People who receives stimulation by surgical techniques, or other padding to help one of the trigeminal to avoid inflammation, are just protecting the weaker of the two, this which started the crisis and thus protected the other. As serotonin levels drop to the level required by the other trigeminal, and without the surgered trigeminal intervention, the crisis will just change the side. We theorize that, since this is less sensitive than the other trigeminal surgery, the crisis may be less important.

Circadian rhythm

The explanation for the circadian rhythm is very simple, and that serotonin levels in the body follow a daily rhythm, marked by changes in daylight by the body directly on the retina (even without light, the day exists for the body but not 24 hours, just some 25 ½, this why “Circadian” in latin, “Circa die”, near a day). The level is highest at noon, and descends slowly as the day goes on. As we approach the darkness, we begin to transform the serotonin into melatonin, and its  levels descends steeply into the night, reaching minimum at mid-dark. After that is replenished very slowly and rises again rapidly from the time we woke up and brought to light the eye, reaching back to maximum (midday) and back to start.

This explains why the most common and practically unavoidable, are crisis at night, especially during sleep. However, if our levels are really inadequate, in the morning, we can also suffer a crisis.

The hypothesis can make predictions about the multiple crises. As already mentioned, while suffering a crisis the platelets release serotonin, which acts sooner or later to produce adequate vasoconstriction and abort the process. After the crisis, the platelet re-capture the serotonin they had released, and when it comes back to the previous level, another crisis will begin.

Exacerbated this process by the reduction of serotonin throughout the day, we could theorize that anyone who suffers a crisis in the first hours of maximum levels, at the zenith of the day, must suffer more crises, because the standards of the rest of the day will always be lower . The elapsed time between two crisis is given by the time it takes platelets to re-capture that released serotonin and reduced to the extent that decreases serotonin in the body. Thus, the time between crisis should decrease as the day progresses, and minimum during the night.

Those who have high average levels, will face only a crisis everyday, in the middle of the night, preferably during sleep. Who has the crisis relatively quickly, well before bedtime, would run greater risk of repeating during sleep. Also it is expected that the time of serotonin reuptake by platelets is proportional to the time of release, that is, the duration of the crisis, so longer crisis should be more spaced in time, and shorter, more together in time.

These considerations are made with the circadian rhythm of serotonin as the only consideration, but not so far from it. Later we will see many other factors that affect serotonin levels and thus the behavior of the disease.

Rhythm circanual

Something that was already known, but it was not scientifically proven, is that the rate of serotonin varies with the seasons. The publication in September 2008 of some studies conducted in Toronto between 1999 and 2003 to a sample of 88 individuals has shown for the first time, no doubt, that the potential binding of serotonin transport are higher in autumn and winter than in spring and summer. Greater potential for the transport union, increased reuptake, less free serotonin available for neuronal transmission.
However, the study shows two things. The first serotonin levels are markedly lower in autumn and winter than in spring and summer. The second, more exciting, there is an inverse correlation between total hours of daylight and time of the sunset with these levels.

So with this, it is easy to predict that arriving the fall and moving  to lower levels of serotonin, some patients begin to experience difficulty, and as the winter comes, the other. Since February, the levels are restored gradually.

Again, there’s other factors involved here that can cause cycles in summer and prevent cycles in winter, but it is already obvious now that a great factor is that the fall / winter, or rather the hours of daylight and sunset hours are a increased factor for the start of the crisis.

Says study (conducted in the northern hemisphere, in Toronto) that in the southern hemisphere should occur equally in respect of the seasons, but with a rotation of six months of the calendar. He also said that he had found a small influence of moisture and age, and virtually none of the temperature.

Episodic and chronic

With our hypothesis in hand, it's easy to settle between people and people with episodic CR CR chronic. The episodic people are those whose serotonin levels are usually sufficient, but a circumstance in which an arrival time to drop these levels begin to engage in crisis and have insufficient levels until the end of the causes why the period of decline, forming the "cycles". The period is par season, but it can also come from other factors such as stress.

The chronically ill are simply those whose levels of serotonin are inadequate throughout the year. It seems valid to be considered that these patients would have more chance of remission in spring and summer and, with medium levels so low, they should be much more likely to suffer multiple crises, especially in autumn and winter. As a corollary, it follows that those who suffer from multiple daily crises, are proving insufficient levels, so it would in turn be more likely to become chronic with others who have more levels, for example, the people who have just a one night crisis.

In any case, given this scenario, there are no chronic or episodic, crisis is always suffered when serotonin levels are insufficient and will forward when eleven. The status of each one is always the circumstance of the moment, so that expressions such as "move to chronic" or "chronic", lack of the meaning they have in other areas of medicine, where the essential is the future remain. Here, a so-called chronic could stop their attacks from one day to another if it can raise its levels of serotonin.

Abortion: Oxygen and triptans

The only two known abortifacients, leaving aside various drugs, the triptans and oxygen. In neither case is known with certainty of their action, although it is accepted that in both cases it’s due to produce significant vasoconstriction, which would always end a crisis that is not excessive vasodilatation

As a crisis begins with a low level of serotonin, and that this level is not replenished by any means, only to be expected after the use of one or the other is that after a while and dismissed its impact, the crisis is restarted and even more strongly, as for the beneficial effects of the vasoconstrictor serotonin levels continued to decline.

There are two possibilities for this happening. The first is that in the time it takes to abort the crisis, it has freed enough to replenish serotonin levels and thus do not fall into a new crisis. This is more possible in patients of a single crisis that in the multiple, because this brief on first can allow replacement levels enough to not incur in another crises until the next day, making it possible more than a partial replacement of vasoconstriction over time are sufficient to avoid a reply. The latter, however, still suffering from the crisis not entirely replenished enough to prevent the next, so that the suffering resulting from the partial replacement of a crisis aborted early, can hardly avoid the effects following cessation of abortion.

Another possibility is that the use of an abortion is performed at night so that when the effect ceases, the levels of serotonin are replenished by its daily cycle.

Conclusions

Seems not to have found a cure here. If the problem is caused by a nerve, say, faulty, we are very far from being able to fix it with the knowledge of medicine today. So put this hypothesis to be adopted in one or more of the following measures:

1) Improving the status and situation of the nerve.
2) Increased levels of serotonin
3) Preventing falls in serotonin

Will be in another document in which I will enumerate and explore the means by which these objectives could be achieved, but we can not ignore the undisputed fact that serotonin levels in the body are good (except dysfunction), however by a good reason that currently only the body knows. Artificial lift will always disrupt our delicate neurohormonal balance, with unpredictable consequences.

There is also the added difficulty of homeostasis, the actual and expected reaction of the body who will try sooner or later to regain its previous situation.

It should, however, take a first step, without risk, and would be beneficial, measures to ensure that the body produces all that want to produce serotonin, ie, to avoid any gaps that are hindering the normal process the body. Not expected here, trying to cover deficits, homeostasis.

Introduction

We start from the assumption that the central problem is a particular sensitivity of the trigeminal nerve, this will produce the inflammation even with not excessive, high, vasodilation levels.

In this situation, the levels of serotonin would be critical for avoiding crises, since it is responsible for vasoconstriction of the major cranial arteries through its receptors 5HT1D. But in this situation must be very vigilant that our efforts to increase levels of serotonin are against the smooth and delicate balance that maintains the body, so the body will fight, and successfully, against the changes that we make (homeostasis) in many ways, even to reduce the density of receptors, so that in the medium term, the battle is lost.

In principle, therefore, the chances would be at least the following:

1) Stabilize the trigeminal, reducing its sensitivity. Search methods or drugs that lead to improvements in the nervous system.
2) To increase the synthesis of serotonin. Based on the cycle of production, supply of raw materials and conditions necessary for their synthesis.
3) Avoid the overall decline in levels. Avoiding the factors which, even with an unknown mechanism, can reduce their levels.
4) Avoid storage. Some substances (SSRIs) may compete for transport by increasing serotonin free.
5) Improve the effectiveness of its action. Increasing the density or sensitivity of their receptors 5HT1D responsible for vasoconstriction.
6) Reduce its transformation into melatonin.

The synthesis of serotonin

Serotonin is synthesized in the body from tryptophan in a transformation that includes an intermediate product prior to serotonin, 5-HTP, and a derivative of it, melatonin. The amino acid tryptophan is an "essential", it means that it  need to be ingested in the diet because the body is unable to synthesize them from other substances.

Only the 2-5% of tryptophan is dedicated to producing serotonin. Other routes include the conversion of Tryptophan in vitamin B3, if needed, and a majority way, the degradation through the T-Pirrolasa, which degrades tryptophan preventing it is transformed into serotonin. There are at least two factors that directly influence the segregation of T-Pirrolasa.

The first is a self regulatory mechanism that increases the production of T-Pirrolasa to an excess of tryptophan.

The second is the presence of cortisol. Cortisol is generated in situations of stress, and its main mission is to provide glucose to the brain even at the expense of the death of any other cell group and regardless of any other circumstance. The problem is that your cortisol level goes up quickly, but it’s slow to download, so if the situations of "stress" are continuing daily, we can reach a state of permanent high levels of cortisol, which is essentially what qualifies it as a disease of stress. Cortisol affects the synthesis of serotonin by increasing the production of T-Pirrolasa and, moreover, increases the avidity of its reuptake platelets, increasing storage and decreasing free serotonin.

Finally, in the absence of daylight, the body begins to transform the free serotonin to melatonin, reducing serotonine to minimum levels at mid-day diary of darkness, with maximum levels at mid-point of light daily.

Proposed method

In light of this scenario, the start of a cycle is not due to a single cause but a combination of a large number of possible circumstances leading to the decrease in serotonin. Chemicals such as spicy additives, mature cheeses, etc.., Would have their own mechanisms for inducing the crisis remained out of this discussion.

If we manage to remove from the equation one or more causes of declining levels, we could improve the quality of life, and in some cases, even avoid cycles. This will depend on how each has reduced these levels. The chronic, for example, have extremely low levels all year, so to them, this dynamic could promote pain-free periods, recessions, especially in the most favorable seasons for this: spring and summer

Please note: this is a theoretical discussion, if you want to implement it should do so with the knowledge and monitoring of a medical practitioner ..

Stabilization of the trigeminal

Besides the possibility of ingesting drugs that improve and protect the nervous system, little to suggest this. Should be avoided, at least, direct actions on the nerve through its branches, acting quickly to any pain in the ear to prevent the progression of infection and keeping  your teeth healthy, avoiding interventions in when in cycle.

Increased synthesis of serotonin

In general terms, not to deepen, the main elements involved in the synthesis of serotonin are: Tryptophan (precursor), and vitamins B2, B3 and B6, and magnesium. As with any chemical process, the amount of product obtained depends on the scarcest of the components involved, which is called the "limiting factor." We must therefore raise the levels of our limiting factor, but how to know whom or what each one?.

The proposal is to improve the diet to the disposal of tryptophan (banana, whole grains, turkey, eggs, milk, ...) to take a vitamin B-complex that includes significant doses of B2, B3 and B6 and Magnesium supplement, all at a time.

The effects should be visible immediately, at most two or three days. If this crisis does not improve, probably all of these components were well and their levels of intake is useless, because the limiting factors were endogenous (eg, T-Hydroxylase essential), otherwise there will be time for eating better and selectively determine which, or which were actually the limiting  factors.

Nevertheless, so that if later cycles suffer more intense than usual, repeating the intake to ensure that this road is completed.

Prevent the overall decline in levels

There are two main causes of the reduction in serotonin levels when the elements necessary for its synthesis are available. The first, scientificly studied, and with unknown cause, the arrival of autumn / winter and with them the decline in hours of light and reducing the hours of sunset, compounded by the energy savings time change. The second, the increased presence of T-Pirrolasa (which degrades tryptophan otherwise), mainly due to excesses of Tryptophan and the presence of cortisol.

The first case, the winter could be avoided with full spectrum artificial lighting and adequate lumens. I initiated the investigation of this route, but unfortunately will have to wait for next fall to do such tests.

The second is the greatest number of cases. The most direct is the stress that generates a direct cortisol. I must clarify here that I do not mean to stress and strengthened, but also point to moments in what could be defined as "the observation that in the near future, near or far, we will have a lost of quality of life." This simple observation leads the generation of cortisol. Fall outside the scope of this shock, strong emotions or impressions. We talked about things such as petty nuisance bear situations (heavy conversations, sounds, images, etc..) Or overwhelmed by the intense observation of the advent of serious future problems (loss of job, leaving a couple, including the arrival of a crisis ).

The last factor is hypoxia, decreased oxygen, which immediately generated large amounts of cortisol. Hypoxia occurs in many cases, such as during sleep (especially in the REM stage), and it’s facilitated by smoking. Thus, the recommendations in this chapter are:

-      Protect the helpless. Take things more calmly, take the adverse circumstances as soon as possible, making decisions and determinations to be taken, but without thinking about it for a while.
- Avoid air pressure decreases. Flying by plane or travel to high altitude geographical points.
- Avoid exposure to polluted environments in any manner, including the worsening air. Fumes, odors or unpleasant penetrating, saturated local small or poorly ventilated areas.
- You can fit here the use of products such as Anacervix (vincamine + Piracetam) or extract of Ginkgo Biloba, which seem to have special properties to improve oxygenation neuronal (check with your doctor)

Avoid storage

The storage of serotonin is produced primarily by its reuptake by 5HT2A receptor / C. Platelets are the main resource of reuptake of serotonin. The intensity of this uptake increases in the autumn / winter, promoting the decrease of free serotonin. The measures in this important issue go through the use of pharmaceutical products (selective inhibitors of serotonin reuptake or SSRIs) more or less powerful:

- A first approximation fairly innocuous (sold without prescription) may be the St. John's Wort (Hypericine), which is also attributed to lower cortisol properties, which would give an extra help in case stress.

- The second, a direct ingestion of SSRIs would be more powerful, of which the best known is the fuoxetina (Prozac). Check with your doctor.

Improve the effectiveness of its action

This section would be to increase the number (density) of receptors 5HT1D or improve their functioning (increase sensitivity). They say that’s what Kudzu does, and for nearly a year, Lilly said the’ve synthesized a peptide that achieve this effect, watch for a year and study its possible sale. We still must wait.

Reduce its transformation into melatonin.

This is where the ambient light acts. Each day at sunset, the body begins to produce melatonin, which increases at the expense of its precursor, serotonin, which drops quickly, reaching minimum in the first REM stage of sleep. This process seems to be conditioned not only by light but also by the presence of intense magnetic fields that hinder this transformation. Given that magnetic fields must be all about, I can think of only one recommendation in this chapter.

Sleep with light. It is shown that the synthesis of melatonin is less if light is still perceived in the eye during sleep. Therefore, avoid sleeping in total darkness, do so with higher clarity that allows you to get to sleep. Ensure that daylight reaches your eyes as soon as possible. It suggests sleeping with the blinds open under natural light, night and day.

Other methods pharmacists (including external ingestion of melatonin synthesis to prevent internal synthesis), I do not want to mention here.

Homeostasis

With all this, there are many ways of combating the CR, most of them can run concurrently. But let us not forget that the body no longer fits, for example, synthesize substances that are provided externally, just  to compensate for the increase. In this sense it is curious to note that the mechanism  of the action of intake B3 or melatonin would be just as homeostasis, the body would cease to synthesize to equilibrate thereby not spending  tryptophan (case B3) or serotonin (if melatonin ).

Interesting - will have to digest it over time. I can see that lots of thought has gone into it, and it seems to be a good starting point for discussion.

The one thing that doesn't fit entirely is the "reduce its (serotonin's) transformation to melatonin" ... first, we know that melatonin can be a good treatment. Second, we know that most clusterheads have low levels of melatonin.  Third (and this is personal, but might apply to some others), I pretty much always get hit in summer - when days are longest and my exposure to light is greatest.

Also, I would add an imbalance of excitatory/inhibitory neurotransmitters to the picture.  Gaba and taurine make nerves less likely to fire, while glutamate/nmda make nerves more likely to fire, and an imbalance here makes the trigeminal less stable in CH in my understanding.

First, thanks for taking the massive amount of time it must have taken to research and produce this thesis. WOW. Wish I had the technical background to participate in this kind of forum. Nothing but good can come out of a discussion like this. It's this kind of research that'll someday stumble on a real cure.

Joe

You mention T-Hydroxylase as something that changes tryptophan/serotonin levels. What about other enzymes that do the same? Drinking alcohol greatly increases liver tryptophan pyrrolase activity (which breaks down tryptophan), and alcohol is the most identified trigger.  Also, there is tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase.

Along with lowering the levels of tryptophan and serotonin, these enzymes also create new chemicals (kynurenine and its related compounds like kynurenic acid and 3-hydroxykynurenine). These kynurenines may have their own role in promoting CH. For instance, the wikipedia page says that kynurenine is associated with tics, and I tend to get twitches (maybe tics?) before and during a cycle. Coincidence, maybe, but twitches and tics can be a sign that the nerve fires too much.

Some people have reported benefits from 5-htp to increase tryptophan/serotonin, but others get hit harder when taking 5-htp. This could be from an increase in kynurenines that result from taking 5-htp alone, when the body is set to produce kynurenine.

Random association that floats to mind: Indoleamine 2,3-dioxygenase can be inhibited by propolis (bee glue) - this might be a potential therapy, although if there is pollen in the propolis (unpurified), it could cause allergies.

You link hypoxia to cortisol, here is another possible link: there is a marked increase in kynurenines after hypoxia or ischemia. Indoleamine 2,3 oxidase increases after oxygen deficit.

Niacin has been suggested to inhibit kynurenine synthesis.

This abstract was written in a style that is a little difficult ... but possibly useful info when decoded.


Quote:

Immunobiology. 2009;214(2):129-34. Epub 2008 Aug 26.    Immunomodulatory effects of Turkish propolis: changes in neopterin release and tryptophan degradation.    Girgin G, Baydar T, Ledochowski M, Schennach H, Bolukbasi DN, Sorkun K, Salih B, Sahin G, Fuchs D.    Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.    In most of the diseases which are considered to benefit from propolis, cellular immune reaction is activated, neopterin levels in body fluids are increased and enhanced tryptophan degradation is observed. In this study, the immunomodulatory effects of six Turkish propolis samples were evaluated by using the in vitro model of peripheral blood mononuclear cells (PBMC). Concentrations of neopterin, tryptophan, kynurenine and pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were determined and also the viability of the cells was checked with trypan blue and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test. In PBMC treated with mitogen phytohaemagglutinin, neopterin production and tryptophan degradation by enzyme indoleamine 2,3-dioxygenase (IDO) as well as release of cytokines was significantly enhanced and upon treatment with propolis extracts all these effects were dose-dependently suppressed. Results show an immunomodulatory effect of propolis extracts which includes down-regulation of IDO activity. IDO enzyme is considered to play an important role in the development of immunodeficiency and neuropsychiatric symptoms in patient with chronic inflammation. The suppression of tryptophan degradation by propolis extracts may therefore be related with some of its beneficial health properties in humans.    PMID: 19167991 [PubMed - in process]

5-htp or tryptophan supplements are most likely to help when tryptophan levels are low due to some dietary or absorptive factor, like lactose or fructose intolerance, celiac disease, or other digestive problems.  


Quote:

Scand J Gastroenterol. 2001 Apr;36(4):367-71.    Fructose malabsorption is associated with decreased plasma tryptophan.    Ledochowski M, Widner B, Murr C, Sperner-Unterweger B, Fuchs D.    Dept. of Clinical Nutrition, Institute for Medical Chemistry and Biochemistry, University of Innsbruck, Austria. maximilian.ledochowski@uibk.ac.at    BACKGROUND: Fructose malabsorption is characterized by the inability to absorb fructose efficiently. As a consequence fructose reaches the colon where it is broken down by bacteria to short fatty acids, CO2, H2, CH4 and lactic acid. Bloating, cramps, osmotic diarrhea and other symptoms of irritable bowel syndrome are the consequence and can be seen in about 50% of fructose malabsorbers. Recently it was found that fructose malabsorption was associated with early signs of depressive disorders. Therefore, it was investigated whether fructose malabsorption is associated with abnormal tryptophan metabolism. METHODS: Fifty adults (16 men, 34 women) with gastrointestinal discomfort were analyzed by measuring breath hydrogen concentrations after an oral dose of 50 g fructose after an overnight fast. They were classified as normals or fructose malabsorbers according to their breath H2 concentrations. All patients filled out a Beck depression inventory questionnaire. Blood samples were taken for plasma tryptophan and kynurenine measurements. RESULTS: Fructose malabsorption (breath deltaH2 production >20 ppm) was detected in 35 of 50 individuals (70%). Subjects with fructose malabsorption showed significantly lower plasma tryptophan concentrations and significantly higher scores in the Beck depression inventory compared to those with normal fructose absorption. CONCLUSIONS: Fructose malabsorption is associated with lower tryptophan levels that may play a role in the development of depressive disorders. High intestinal fructose concentration seems to interfere with L-tryptophan metabolism, and it may reduce availability of tryptophan for the biosynthesis of serotonin (5-hydroxytryptamine). Fructose malabsorption should be considered in patients with symptoms of depression and disturbances of tryptophan metabolism.    PMID: 11336160 [PubMed - indexed for MEDLINE]

I think we should talk a little about the metabolism of tryptophan to clarify the situation. Tryptophan can be mainly degraded at intestine, liver and brain in several "ways":

1) Way of serotonin and melatonin. Tryptophan is oxidized by the enzyme Tryptophan hydroxylase-(T-hydroxylase) to form 5-Hydroxytryptophan (5HTP), which is decarboxyled by decarboxylase to 5-hydroxytryptamine (5HT or serotonin). Finally, serotonin may be degraded by MAO to 5-hydroxy-Indalate (5HIAA) or transformed by action of hydroxy-indole-methyltransferase to melatonin.

2) Way of kynurenina. Tryptophan is oxidized by the T-2 ,3-dioxygenase (also called T-dioxygenase or T-pirrolasa) or Indolamine 2.3-dioxigenasa to produce different products for all with the kynurenina.

3) Way of indoles. It is produced by the action of bacteria in the gut.

4) Production of B3 (niacin, nicotinic acid). Used 50 mg. tryptophan to produce 1 mg. B3. The need of tryptophan daily minimum stipulated by 175-250 mg. The Western diet provides 600-1200 mg .. The daily requirement of B3 is set to about 16 mg. To produce this amount would be spent 800 mg. tryptophan, almost all of ingestion.

monty wrote on Feb 16^th, 2009 at 9:13am:

The one thing that doesn't fit entirely is the "reduce its (serotonin's) transformation to melatonin" ... first, we know that melatonin can be a good treatment. Second, we know that most clusterheads have low levels of melatonin.  Third (and this is personal, but might apply to some others), I pretty much always get hit in summer - when days are longest and my exposure to light is greatest.

First, melatonin is a good treatment because his administration avoids the use of serotonin in their production. Proof of this is a testimony of someone who, after consuming melatonin during two years, free of crisis and unable to obtain it, was recovering years the pace of that dream had always been normal, and suddenly it was not. And it took a long time to recover with normal sleep, and it was because the body was accustomed to receive it and had abandoned their production. Serve this testimony for those using today.
Second, one can not have good levels of melatonin with low levels of serotonin, since the former is produced from the second. It's normal.
Third, the study concerns the potential union of serotonin transporter. This potential is an important factor in the levels of free serotonin, but not the only or decisive. Their synthesis is more important than the level of storage. Give figures for the potential binding of a carrier increases 15/20% in autumn and winter. But the daily cycle decreases by 80% the level of midday at overnight. By this I mean that the station aid, but there are many, many causes of lower levels. I myself always have a winter cycle and often a more gentle cycle in March / April.


monty wrote on Feb 16^th, 2009 at 9:13am:

Also, I would add an imbalance of excitatory/inhibitory neurotransmitters to the picture.  Gaba and taurine make nerves less likely to fire, while glutamate/nmda make nerves more likely to fire, and an imbalance here makes the trigeminal less stable in CH in my understanding.

Had already said that the chemicals away from the discussion, it would be great to try to explain the mechanism by which drugs we are prescribed. But I lack the capacity to do so, although I will continue studying and I do not have too much free time.


monty wrote on Feb 16^th, 2009 at 10:14am:

You mention T-Hydroxylase as something that changes tryptophan/serotonin levels. What about other enzymes that do the same? Drinking alcohol greatly increases liver tryptophan pyrrolase activity (which breaks down tryptophan), and alcohol is the most identified trigger.  Also, there is tryptophan 2,3-dioxygenase and Indoleamine 2,3-dioxygenase.

Tryptophan 2,3-dioxigenasa is pirrolasa-tryptophan. It's called the two ways. The Indolamina 2.3-dioxigenasa (IDO) is controlled by the immune system. Do not get that far, at least for now.


monty wrote on Feb 16^th, 2009 at 10:14am:

Along with lowering the levels of tryptophan and serotonin, these enzymes also create new chemicals (kynurenine and its related compounds like kynurenic acid and 3-hydroxykynurenine).

Rising levels of kinuerinina shows, however, that this tryptophan is metabolized by this route and therefore is decreasing serotonin pathway.


monty wrote on Feb 16^th, 2009 at 10:14am:

Some people have reported benefits from 5-htp to increase tryptophan/serotonin, but others get hit harder when taking 5-htp. This could be from an increase in kynurenines that result from taking 5-htp alone, when the body is set to produce kynurenine.

No, the kynurenina precursor is tryptophan, no 5-HTP. The 5-HTP can only lead to serotonin.


monty wrote on Feb 16^th, 2009 at 10:14am:

Random association that floats to mind: Indoleamine 2,3-dioxygenase can be inhibited by propolis (bee glue) - this might be a potential therapy, although if there is pollen in the propolis (unpurified), it could cause allergies.

Know at this time which of the two enzymes that cause the path of kynurenina was the most active. I do not know what the propolis.


monty wrote on Feb 16^th, 2009 at 10:34am:

You link hypoxia to cortisol, here is another possible link: there is a marked increase in kynurenines after hypoxia or ischemia. Indoleamine 2,3 oxidase increases after oxygen deficit.

This is a consequence and not a cause. The cortisol Hypoxia occurs, it raises the T-pirrolasa and because it produced more kinureninas


monty wrote on Feb 16^th, 2009 at 10:34am:

Niacin has been suggested to inhibit kynurenine synthesis.

If there is an abundant presence of B3, tryptophan is not used for their synthesis, and thus remains free to both the tryptophan kynurenina to the path of the hydroxy-indoles. I can't agree this point.
-----------------
After all this, and dealt with a little more depth, it is clear that tryptophan we eat can become kuynurenina, serotonin, or niacin (B3). We must therefore avoid the transformation in B3 (eating) and kynurenina (avoiding the T-Pirrolasa, which, incidentally, is not only due to increased cortisol, but also of pyridoxine).

Regards

Its going to take a bit of time to study this.  An impressive amount of research, sir.  Thank you.

PFDAN y'all
kathy

Have been following this with interest.

Many thanks, gentlemen.  I've often wished we had more discussion about causes here.

Best wishes,

George

:-X [smiley=oops.gif] [smiley=wow.gif]

Good discussion ... replies to some of your points:  

... one can not have good levels of melatonin with low levels of serotonin, since the former is produced from the second. It's normal.

I agree that we can't have normal levels of melatonin without normal levels of serotonin.  But I disagree with your recommendation #6, "Reduce its (serotonin's)  transformation into melatonin."  Melatonin is low in clusters, and should be raised.  If serotonin is brought up to normal levels, I don't think anything should be done to prevent it from being turned into melatonin.

Had already said that the chemicals away from the discussion, it would be great to try to explain the mechanism by which drugs we are prescribed.

Taurine and GABA are amino acids and neurotransmitters used by the body to fight some of the components of clusters. These fit in with strategy #1, stabilize the trigeminal.



Rising levels of kinuerinina shows, however, that this tryptophan is metabolized by this route and therefore is decreasing serotonin pathway.

I agree - it both reduces serotonin, AND it increases kynurenines, which themselves may be bad for cluster headaches.  (Which is why I am interested in things like propolis which can reduce the enzymes that take tryptophan away from serotonin).

Another compound that inhibits these enzymes is brassinin, from broccoli, cabbage and related plants. There is a synthetic compound based on tryptophan that reduces the enzymes, but probably not available. And nitric oxide has a role in inhibiting IDO and pyrrolase, but I'm not going to mess with nitric oxide levels at this point.  

the kynurenina precursor is tryptophan, no 5-HTP. The 5-HTP can only lead to serotonin.

Yes, 5-htp is one step away from serotonin, and most 5-htp gets converted. So in that sense, it may be a better thing for people with CH to take...

But the reports of some people getting worse with 5-htp indicates that it is not just low serotonin levels ... the serotonin-2 receptors are too active, while the serotonin-1 receptors are not active enough.  


This is a consequence and not a cause. The cortisol Hypoxia occurs, it raises the T-pirrolasa and because it produced more kinureninas

You may be right on that, although the increase in the enzymes occurs very rapidly with hypoxia - I think that cortisol is one of several things that increase the kynurenine forming enzymes.

(Niacin has been suggested to inhibit kynurenine synthesis.) If there is an abundant presence of B3, tryptophan is not used for their synthesis, and thus remains free to both the tryptophan kynurenina to the path of the hydroxy-indoles. I can't agree this point.

The nicotinamide form of niacin has a direct effect in blocking the increase of the pyrrolase enzyme in the liver (at least in lab animals) ... see the article "The regulation of rat liver tryptophan pyrrolase activity by reduced nicotinamide-adenine dinucleotide (phosphate). Experiments with glucose and nicotinamide", pubmed ID 8041.  

Some researchers have suggested that ordinary niacin (at high doses) has a feedback function that does the same thing, although that has not been proven.

While following up on things in this discussion, I noticed a large number of articles related to inflammation causing an increase in the production of kynurenines and a decrease in serotonin.  Most notable include various infections and chronic inflammation, drinking alcohol, possibly smoking (lung inflammation decreases tryptophan, increases kynurenines).  Although there were no published studies I saw, I also wonder if calorie restriction has an effect.

Another possible dietary strategy for dealing with these enzymes that rob the body of serotonin is rosmarinic acid (found in rosemary herb, but even higher levels (and less soapy!) in Lemon Balm herb (Melissa officinalis)). See the article "Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells", pubmed ID 17229401.  Rosmarinic also has beneficial effects in lowering anxiety. One drawback is that lemon balm may lower thyroid function somewhat - good for some, indifferent for others, but chilly for those whose thyroid is already low.

But I disagree with your recommendation #6, "Reduce its (serotonin's)  transformation into melatonin."  Melatonin is low in clusters, and should be raised.  If serotonin is brought up to normal levels, I don't think anything should be done to prevent it from being turned into melatonin.

The difference we have is the departure point. You part from that melatonin is necessary, that is low and that it is necessary to raise it. I part from that what is low is the serotonin and that's why melatonin is low, and that no matter it'is low. This would in principle affect only to sleep and immune system in the long run; there is no direct relationship with the CH.

And you can avoid serotonin becoming melatonin, naturally, giving melatonin externally. As you take it, the body reduces its endogenous production, reducing the consumption of serotonin. One might also play with light during the day and night, but should be considered if the impact of this measure would be relevant. I have a testimony of someone whose "siestas" always started a crisis, but now he's doing "siesta" with the light on, an he no longer suffers this crisis.

But here is a point to reach an agreement. I say that melatonin is not involved in the CH, its reduction is only a reflection of decreased levels of serotonin. It has no more importance and no other role here.

It would be great to try to explain the mechanism by which drugs we are prescribed

It's a good idea to start thinking about. I had some ideas, if you have time (and I), we can do it in the future.

I agree - it both reduces serotonin, AND it increases kynurenines, which themselves may be bad for cluster headaches

As with melatonin, we disagree on the same type of question, I do not think that is a factor kynurenina of CH. I think that their levels are a consequence of, and show, what's happening at the level of the metabolism of tryptophan. However, at this point at least we agree on avoiding the formation of kynurenina.

Yes, 5-htp is one step away from serotonin, and most 5-htp gets converted. So in that sense, it may be a better thing for people with CH to take...

But the reports of some people getting worse with 5-htp indicates that it is not just low serotonin levels

This topic has me curious result ever since. The most logical thing is that 5-HTP feel good, but really are who actually not. There is however a logical reason for it, and that these people would have trouble running the phase transformation of 5-HTP to serotonin. Recipients in all this has much to say, but I do not miss the blame for this so directly.

The nicotinamide form of niacin has a direct effect in blocking the increase of the pyrrolase enzyme in the liver

Ok, did not know. Noted. In this case, the B3 should be doubly beneficial. Inhibits T-pirrolasa and not spent tryptophan in it's synthesis. The truth is that to me it has been always great.

-------------------

When I have time i'll post a resume of the elements of recommendation #2 and actions to take over each one. This could be a good discussion with practical results.

Best regargs.

WOW. Good stuff. thanks :)

OK, I am starting to understand you views better, although some things I disagree with.


This would in principle affect only to sleep and immune system in the long run; there is no direct relationship with the CH.

I disagree here - I don't see any reason to limit the effects of melatonin to sleep and immune functions.  It seems to be involved in many other important functions, including neuroplasticity and neuroprotection.  Melatonin can also affect the PI3K pathway.

Melatonin itself affects the serotonin receptors.  See the article "Melatonin potentiates 5-HT(1A) receptor activation in rat hypothalamus and results in hypothermia." (pubmed ID 12121481). This article also states that the effects of melatonin can be blocked by stimulating the 5-ht2 receptors ... this supports my idea that it is not only the amount of serotonin (which I agree is usually too low), but also the number, type and functioning of the different types of receptors.  Triptans and other drugs stimulate the 5-ht1 receptors and turn off clusters (at least in short run), while blocking the 5-ht2 receptors (kudzu, olanzapine, ergotamine, psilocybin, etc) can also turn the pain down or off.

And you can avoid serotonin becoming melatonin, naturally, giving melatonin externally. As you take it, the body reduces its endogenous production, reducing the consumption of serotonin.

When melatonin first became popular in the US (early 1990s), I remember reading an article that said taking extra amounts of it (exogenous) did not cause the body to make less - ie, addiction and withdraw were not seen as likely.  Not sure if that is true or not ... will check. While abrubtly stopping exogenous corticosteroids, morphine, testosterone, etc leads to an obvious deficiency, this has never been noted with melatonin to the best of my knowledge.  


In other news, I dusted off a program I wrote a while back to search the medical research - it is now looking for connections between things like IDO/pyrrolase and a few thousand herbs and foods. Will check the results of that tomorrow.

While waiting for a more complete answer, for lack of time, I just want to fix an error in my package. The nicotinamida (B3) is synthesized from tryptophan via the kynurenina. This means that their synthesis should reduce kynurenina, like you said. The process is:

tryptophan + TDO = N-formilquinuernina + B9 => Quinurenina + oxygenase => 2-amino-3-carboximucónico + Alanine => Quinolinate => Nicotinate => Nicotinamide.

So we have actually two tracks: the kynuerina and the indoles.

Sorry. Can you see how discussing show mistakes?. It's right, that.

Ok - a few other possible therapies.

At least 2 probiotic bacteria (Bifidobacterium adolescentis and Bifidobacterium longum) reduce tryptophan pyrrolase activity in the gut.

Shiitake mushroom stimulates Bifidobacteria breve and Lactobacillus brevis, and leads to reduced levels of tryptophanase in the gut. PMID: 18982487

Curcumin (turmeric) decreases conversion of serotonin to 5-HIAA (MAO inhibitor?) Curcumin also has beneficial effects on the balance of 5-ht1 and 5-ht2 receptors (stimulates -1 and inhibits -2). For a variety of other reasons, curcumin seems like a potential good treatment. Am working on a longer write-up of curcumin, but will throw it out here.

"Excessive doses of retinol (vitamin A) reduces liver t-pyrrolase ... not sure how toxic these 'excessive' levels are.  PMID 17942093.

Will keep sifting through the list to see what else might be significant.  

Firstly, thank you very much for the information and interesting discussion.

However, I am a bit lost as to how it all can be applied practically to help CH ?

That remains to be seen. If something seems to have the right effects in lab studies and it works dramatically enough to make an immediate difference (as did Kudzu), then it may become part of the arsenal against CH.  If something takes longer to kick in and/or only leads to a modest reduction, it may be difficult to pick up on.... someone tries it, and it maybe sorta improved things, but a cycle could have been winding down etc etc.

But I think that there are things out there waiting to be discovered (by anyone) that can reduce CH pain. Having a model or understanding of the disease lets us search for safe and effective treatments. If a serotonin deficiency is a main cause of clusters (as was asserted above), there is much that can be done in response to that.

wrote on Feb 18^th, 2009 at 3:40pm:

Firstly, thank you very much for the information and interesting discussion. However, I am a bit lost as to how it all can be applied practically to help CH ?

Hi all, knowledge is power, and altough I barely understand a part of what is writen here, I believe the U in OUCH means Understanding, and that is what I'd like to do.
May be someday, someone, after reading one of those posts, will tie them and will find the ......(can I say cure).
Saludos
Poli

monty wrote on Feb 18^th, 2009 at 3:52pm:

... If a serotonin deficiency is a main cause of clusters (as was asserted above), there is much that can be done in response to that.

That aspect of CH has been looked at and many treatments have been based on that but so far the results are mixed. CH is a very complex condition and simply raising serotonin level or maintaining serotonin level has not given us the answer.

The serotonin relevant to CH is the intracranial one, which is only a very tiny amount compared to the serotonin in the rest of the body, especially in the digestive system. There is a very strict control of the amount of serotonin in the brain, regulated by the hypothalamus. External factors that affect the overall serotonin level in the body does not have much direct effect on that in the brain.

I totally agree that it is important to search for influential and causative factors in order to come up with possible treatment plans. However, one needs to be able to evaluate the practical implication of each hypothesis. One can never get  funding for a proper study or lab experiment unless practical applications can be demonstrated.

So far, the hypothesis discussed failed to address one of the most peculiar and important aspect of CH : the clockwork timing of the hits and the seasonal feature of the cycle. Is there any way you can reconcile the above hypothesis to this aspect of CH ?

On another point, although the level of cerebral serotonin is relatively stable, and so is the level of melatonin, there is a significant variant present between day and night and even during the awake or asleep state, both levels ebb and flow according to the circadian rhythm. Again this is regulated by the hypothalamus. How do you propose to correct the level of serotonin with regards to this constant variant ?

Please understand that I am criticizing anything or anyone. It is important to discuss and challenge hypothesises so that we can come closer to proving it or disproving it, and in the process, understand the condition better.

Thank you Gonzalo for starting the discussion, I am looking forwards to hearing your views.

This thread was locked up.  Got it fixed...

8-)

...maybe

:-/

yup, it's fixed.

Thanks, DJ - I may have crashed it with too many quotes and not closing the tags ... sorry if that was the problem. Will be more careful.


wrote on Feb 18^th, 2009 at 5:58pm:

That aspect of CH has been looked at and many treatments have been based on that but so far the results are mixed. CH is a very complex condition and simply raising serotonin level or maintaining serotonin level has not given us the answer.

I agree that the serotonin level alone cannot explain everything, which is why I have brought in other factors - the type, number, and sensitivity of different serotonin receptors, for example. Undoubtedly, there are other things (like calcium channels, magnesium deficiency, choline issues, etc), but for purposes of discussion, am focusing on serotonin. We can't consider everything at once (well, some might be able to, but we can only communicate in a reduced, linear fashion which smashes the true form).


Quote:

There is a very strict control of the amount of serotonin in the brain, regulated by the hypothalamus. External factors that affect the overall serotonin level in the body does not have much direct effect on that in the brain.

I don't believe that. It has been shown that a diet low in tryptophan, or lactose or fructose intolerance (which reduces tryptophan absorption) lowers serotonin levels in the blood and is associated with anxiety, depression, and other problems of the nervous system. Because tryptophan must be actively transported into the brain, it is possible that this transmission system can be impaired, or that other amino acids compete with tryptophan and reduce levels.  My worst two years of cluster headaches were when I was living with what (in obvious hindsight now) was an undiagnosed/misdiagnosed fructose intolerance.  Which is not to reduce all clusters to that one theory, merely to accept it may have been an issue for me and some others.


Quote:

...  However, one needs to be able to evaluate the practical implication of each hypothesis. One can never get  funding for a proper study or lab experiment unless practical applications can be demonstrated.

I personally have no plans of jumping through all the hoops required for getting funding for a 'proper' study. While experimental science can be quite useful, my personal approach is to use these discussions as something like the journal Medical Hypotheses - it is mostly paradigmatic examination and thought experiments, but it is a very useful journal. Then I try what works for me, as ultimately, no one cares if a treatment works 40% of the time, or 70% of the time, we care what works for each of us.


Quote:

So far, the hypothesis discussed failed to address one of the most peculiar and important aspect of CH : the clockwork timing of the hits and the seasonal feature of the cycle. Is there any way you can reconcile the above hypothesis to this aspect of CH ? [quote] Yes, this is a good point.  For me, hits are always in summer, when days are longest (and melatonin is lowest). And the same time each day, like a alarm clock. But others may be winter only, or spring and fall, or chronic, or seemingly random. From a big-picture standpoint, I take a cybernetic / systems theory approach to clusters. The brain/body is a complex entity, something destabilizes this system, which at times responds in a regular way, sometimes in a chaotic way.  The encouraging (and discouraging) thing about systems theory is that there can be hundreds of things that make a positive difference, but also hundreds of things that make things worse, and there is no telling which things work for which people. On the other hand, some factors are more central or prime to the mechanism, so these are obviously more important. [quote] On another point, although the level of cerebral serotonin is relatively stable, and so is the level of melatonin, there is a significant variant present between day and night and even during the awake or asleep state, both levels ebb and flow according to the circadian rhythm. Again this is regulated by the hypothalamus. How do you propose to correct the level of serotonin with regards to this constant variant ?

I know of no evidence that cerebral serotonin and melatonin are relatively stable or that they can never be sub-optimal. Also, it has been shown that episodic clusterheads have an abnormally weak melatonin curves (little or no variation between day and night), even when in remission.  Perhaps the most important part of the brain for melatonin is the pineal gland, not the hypothalamus; though there is clearly a functional axis between the two structures.

So I don't believe in that constant variant - the evidence is that the pineal gland and hypothalamus SCN aren't working properly, but no one knows why yet.



Quote:

Please understand that I am (not?) criticizing anything or anyone.

No, I don't take it that way. We are all discussing ideas and sometimes criticizing parts of the ideas and kicking the tires on our conceptual cars, which is good. If an idea is true or useful, it will survive.

First, thanks for the fixing work. Superbe.

Hello, Annsie

I'll try try to give you a global answer while I comment on specific points on your message. It's clear that CH is complex, so here we are crumbling as we can. I don't know what kind of "answer" ar you looking for, I settled myself today with a better quality of life, and now I'm going there.

Nor do I understand on the basis of which states that maintain or increase levels of serotonin did not give the reply. I think, at your words, that already tried to do this, otherwise left to know if it has been really achieved. And no, I think, there's not an "answer", but a long way to go. I share the words of monty: "If a serotonin deficiency is a main cause of clusters (as was asserted above), there is much that can be done in response to that.".

Nor do I share other statements, such as the level of serotonin is strictly controlled, and by the hypothalamus. If you want to comment on where you read this, it would be a good contribution to the discussion, because nothing that I've studied so far supports that idea at all.

Moreover, in the first post I explain the circadian and circanual rhythms based on the hypothesis. It's the first thing I did, it might not please everyone and of course it's subject to discussion, but I did. Please review it.

And if we withdraw the alleged control of the hypothalamus, and we agree that lower levels at night (up to 80% lower than on the day), and if I say that 2% of serotonin is in the brain, 8% in platelets and 90% in the intestine and that we are interested in 2% and 8% and not only at brain's 2%, we can continue to seek ways to increase these levels.

But again as we move through the discussion we'll arrive to practical conclusions, but surely not "the answer" yes, but, as I said, to a better quality of life. I hope.

Salut.

Hello again. Here's a partial info to polish.

The hydroxy-methoxy-indoles pathway of the triptofan

Apart from that we should increase the global availability of tryptophan, and the specific availability  to this pathway (complex and relevant issue that we still need to discuss), here is a summary of the metabolism of tryptophan via the hydroxy-methoxy-indoles and indoles derived from them.

This pathway consumes 3% of ingested tryptophan (from 2-5%). The process is as follows:

1) Tryptofhan + enzyme T-tryptophan hydroxylase (TPOH) + cofactor tetrahidrobiopterín => 5-Hydroxytryptophan (5HTP).

2) 5HTP + 5-Hydroxytryptophan decarboxylase + cofactor priridoxal phosphate => serotonin (5HT).  Note: pyridoxine phosphate (vitamin B6) + Riboflavin (vitamin B2) => pyridoxal phosphate.

3) The serotonin can follow these paths:

   A) 5HT + monoamine oxidase (MAO) + AldDH? => 5-hydroxy-indole acetic acid (5-HIAA).

   B) 5HT + monoamine oxidase (MAO) + ADH? => 5-hydroxy-tritofol

   C) 5HT + ariralquilamina-N-acetyltransferase => N-acetilserotonina + indoxi-indol-O-methyltransferase => Melatonin (MT)


Since if we wanted to enhance the path 1-2-3C, we should:

1) Increase or not decrease (TPOH) and (tetrahidrobiopterin)
2) Increase or not decrease (5-Hydroxytryptophan decarboxylase) (B6) and  (B2)  (This last does pridoxina phosphate => pyridoxal phosphate )
3) Reduce the monoamine oxidase (MAO) to prevent catabolization of seroronina (5HT)  to (5-HIAA).

In short, the question is how to raise (or not fall):

1) T-Hydroxylase (TPOH)
2) Tetrahidrobiopterín
3) 5-Hydroxytryptophan decarboxylase
4) (B6) Pyridoxine phosphate
5) (B2) Riboflavin. Causing pyridoxine phosphate => pyridoxal phosphate

And how to fall (or not raise):

6) monoamine oxidase (MAO) to avoid routes 3A and 3B.

So we can begin to explore how to do these 6 things that We could call “actions on pathway serotonin/ melatonin #1 to #6 “

Comments awaited.

Thank you, This is the best post i seen since i have been part of this site. My only question right now is, if sertonin is the main thought process here, how does mushroom stop so many people with clusters, do the mushrooms raise their sertonin levels? i Will be following this post.  


                   Challening, more assertive.. Coach Bill >:(

So, Monty

Returning to the melatonin (I know I am recurrent), I agree that it's unsafe to reduce their levels, due to the important role of it at so many levels, but I can not yet directly linked to the CH, only because the the indirect consumption of serotonin.

This is because the times were more prone to crises are precisely the times in which more melatonin is produced. At night and in winter. I've seen charts of annual levels of melatonin (study in France) and are near reversed to those of serotonin. It increases in summer (peak stage) and winter (high peak) and minimum in spring and autumn, more peak for the old people than for youngers. Also the daily maximum is in the dream. It is understood why I can not see a direct melatonin-CH: ¿more melatonie, more crises? ... .

And one last thing. I can not believe that the body does not decrease the production of melatonin after its exogenous intake. I have already related about the person who took years to recover its all-life "well sleeping" when leaving melatonin after consuming it for two years. And we will investigate a little bit in everything.

Un abrazo.

coach_bill wrote on Feb 19^th, 2009 at 9:20pm:

Thank you, This is the best post i seen since i have been part of this site. My only question right now is, if sertonin is the main thought process here, how does mushroom stop so many people with clusters, do the mushrooms raise their sertonin levels?

WE'll arrive here soon. For the moment i think I've read LSD and Mushrooms have a strong affectation to the serotonin recepeteurs. No much idea at this moment, but I think in this thread we need to pass over nearly all the CH affections, including this one.

Regards

More important, at least as important as the way of tryptophan to serotonin is the road that runs the tryptophan ingested to the brain, facilitating the presence of free tryptophan, tryptophan combined with albumin, which is captured by the pineal (incidentally, the pineal is outside the blood-brain barrier) and improve all these processes.

Then be seen as preventing the tryptophan chooses the path of quinurenina and do to become serotonin.

So the study would have three phases:

1) Study to improve availability of tryptophan

2) Study of inhibition of the pathway quinurenina

3) Study of the enhancement of the serotonin pathway

This done, we can turn to the reuptake, SSRIs, etc. ..

It's right this planning for you???

But with calm, OK? I am making an effort with my time. Pleasant, but one effort.

Gonzalo wrote on Feb 19^th, 2009 at 9:00pm:

First, thanks for the fixing work. Superbe. Nor do I share other statements, such as the level of serotonin is strictly controlled, and by the hypothalamus. If you want to comment on where you read this, it would be a good contribution to the discussion, because nothing that I've studied so far supports that idea at all. Salut.

Hi Gonzalo,

I read about serotonin control in this article:

Solms, Mark (2000) DREAMING AND REM SLEEP ARE CONTROLLED BY DIFFERENT BRAIN MECHANISMS,  Behavioral and Brain Sciences 23 (63)

and from the other articles as quoted in that article.

You may need a subscription or online purchase to be able to access it though.

I have been reading up on pineal gland and REM and nonREM sleep, the bioneurological mechanism of different stages of sleep, not in a CHer but in normal and mentally ill patients. What I read I was surprised to find how much it could be related to CH and the mechanism of CH. However, it is so complicated that it is almost impossible to summarise into an easily understandable presentation.

The level of serotonin and melatonin changes throughout the day and night, according to the circadian rhythm, which in turns is affected both by internal factors such as the hypothalamus and the pineal gland etc , and external factors like the weather, the different seasons etc.

Since personally I am finding it difficult to discern the most important pathway or element, I am hoping that by discussing it with others will make things clearer.

My main interest in to come up with some strong enough evidence that I can present to the specialists at medical conferences to raise their interest, with view to pushing for research. So far, I have not been able to develop a concise enough hypothesis that I can present and defend.

Thanks for helping.

monty wrote on Feb 19^th, 2009 at 8:37pm:

Quote: There is a very strict control of the amount of serotonin in the brain, regulated by the hypothalamus. External factors that affect the overall serotonin level in the body does not have much direct effect on that in the brain. I don't believe that. It has been shown that a diet low in tryptophan, or lactose or fructose intolerance (which reduces tryptophan absorption) lowers serotonin levels in the blood and is associated with anxiety, depression, and other problems of the nervous system. Because tryptophan must be actively transported into the brain, it is possible that this transmission system can be impaired, or that other amino acids compete with tryptophan and reduce levels.  My worst two years of cluster headaches were when I was living with what (in obvious hindsight now) was an undiagnosed/misdiagnosed fructose intolerance.  Which is not to reduce all clusters to that one theory, merely to accept it may have been an issue for me and some others.

Anxiety and depression have been found to respond to medication that raises serotonin such as SSRI. Therefore it was deduced that potentially low serotonin is the cause of anxiety and depression. However, recent studies have found that SSRIs work not by increasing or stablelising serotonin but through the indirect effects of noradrenaline and dopamine.

In CH, simply making more serotonin available with SSRI does not work.

So far, what I have found is that CH can be brought on by many mechanisms. It involves the circulation, the inflammation process, the trigeminal nerve, the autonomic nervous system and the circadian rhythm. However, the evidences seem to point most strongly towards the autonomic nervous system and the circadian rhythm. The hypothalamus and the pineal glands regulate these two.

What seems to happen in CH is either these two glands malfunction all by themselves ( due to genetic predisposition ) or these two glands malfunction due to an abnormal feedback system caused by abnormal levels of certain neurotransmitters.

This model of pathogenesis has been shown to exist in other conditions which also involve similar organs, pathways and neurotransmitters, such as migraines and some mental disorders.

Diet and lifestyle change have been shown to be helpful in those conditions but not as reliable treatment option. I am not saying that they dont help, its just that the level of improvement is not consistant nor significant enough to be deemed therapeutic.

wrote on Feb 20^th, 2009 at 4:00am:

Anxiety and depression have been found to respond to medication that raises serotonin such as SSRI. Therefore it was deduced that potentially low serotonin is the cause of anxiety and depression. However, recent studies have found that SSRIs work not by increasing or stablelising serotonin but through the indirect effects of noradrenaline and dopamine.

SSRIs don't raise the actual amount of serotonin in the body; they only increase the effective level of serotonin in certain areas of certain nerves (and as you noted, that may not even be how they work - it may be indirect effects on other things).  So the fact that SSRIs don't usually improve clusters is good to know, but it is limited in scope.

SSRIs have a very different type of action than a MAO inhibitor or a serotonin precursor or and indoleamine deoxygenase inhibitor, all of which can actually raise the level of serotonin.  And the work on lactose/fructose intolerance shows that some individuals with anxiety/depression do respond quite well to increasing the levels of serotonin in the blood - tryptophan is converted to serotonin, but nor/epinephrine and dopamine require the amino acid tyrosine.



Quote:

In CH, simply making more serotonin available with SSRI does not work.

Again, SSRIs do not make more serotonin available everywhere. They make each pulse of serotonin in some nerves more likely to last longer or be more intense - and they do this by blocking the reuptake in certain nerves.  

When low serotonin levels reduce melatonin production, SSRIs do not necessarily change that. (Some SSRIs do, but they do it indirectly by inhibiting other enzymes, and some SSRIs do not affect melatonin at all.)  On the other hand, taking tryptophan or 5-htp has been shown to raise melatonin fairly consistently, especially when serotonin levels were low to start.


Quote:

So far, what I have found is that CH can be brought on by many mechanisms. It involves the circulation, the inflammation process, the trigeminal nerve, the autonomic nervous system and the circadian rhythm. However, the evidences seem to point most strongly towards the autonomic nervous system and the circadian rhythm. The hypothalamus and the pineal glands regulate these two.

Agree fully. I think the hypothalamus/pineal factors and the serotonin/melatonin factors are close to the center of the mechanism, and as such deserve special attention. But other things can destabilize or disturb the system.


Quote:

What seems to happen in CH is either these two glands malfunction all by themselves ( due to genetic predisposition ) or these two glands malfunction due to an abnormal feedback system caused by abnormal levels of certain neurotransmitters.

One curious thing I came across recently was the idea that the pineal gland can get calcified and less responsive. This can happen naturally, but high fluoride levels are also one way this can happen. Three of us here are from the same small town, which was one of the first to fluoridate water.  Coincidence?  Maybe. I'm sure there are other factors - traumatic injury to the head (I also have that), genetic predisposition, poor sleep hygiene, etc. etc.



Quote:

Diet and lifestyle change have been shown to be helpful in those conditions but not as reliable treatment option. I am not saying that they dont help, its just that the level of improvement is not consistant nor significant enough to be deemed therapeutic.

Agree with you on this for the most part.  Lifestyle can be very important, but it is not always a direct or consistent pattern. We know that what works for some won't work for others.  In a sense this is similar to migraines - 'therapeutics' include the triptans and other quick acting medicines, a few preventives, but lifestyle is even more nebulous and harder to predict, so many throw up their hands with respect to lifestyle modifications.  

monty wrote on Feb 20^th, 2009 at 1:29pm:

SSRIs don't raise the actual amount of serotonin in the body; they only increase the effective level of serotonin in certain areas of certain nerves (and as you noted, that may not even be how they work - it may be indirect effects on other things).  So the fact that SSRIs don't usually improve clusters is good to know, but it is limited in scope. SSRIs have a very different type of action than a MAO inhibitor or a serotonin precursor or and indoleamine deoxygenase inhibitor, all of which can actually raise the level of serotonin.  And the work on lactose/fructose intolerance shows that some individuals with anxiety/depression do respond quite well to increasing the levels of serotonin in the blood - tryptophan is converted to serotonin, but nor/epinephrine and dopamine require the amino acid tyrosine.

Monty, you need to go back and read about neurotransmitters and synaptic transmittions again because what you said there is not quite correct. SSRIs does affect the level of serotonin AVAILABLE at the synapses of ALL of the nerves which use serotonin as a neurotransmitter.

MAOI and IDI have a similar effect. They block the breakdown of the precursors of serotonin allowing more to be available at the synapses.

The TOTAL amount of serotonin is regulated by a feedback system controlled by the hypothalamus and/or the pineal gland.

BTW, I am interested in what you have read relating to the work on lactose/fructose intolerance. Would you be able to cite some references for me please ? thank you. I have not yet looked in that direction.


monty wrote on Feb 20^th, 2009 at 1:29pm:

Again, SSRIs do not make more serotonin available everywhere. They make each pulse of serotonin in some nerves more likely to last longer or be more intense - and they do this by blocking the reuptake in certain nerves.

SSRIs make more serotonin available and for longer at EVERY synapse of ALL the nerves that use serotonin as a neurotransmitters. Thats why SSRIs have so many side effects.

Here are some links on sugar malabsorption and serotonin and related conditions, along with some other reports that simply consuming more beta-lactalbumin (a milk protein) can increase serotonin levels and improve mood.

Malabsorption of carbohydrates and depression in children and adolescents. PMID: 15861016

Fructose malabsorption is associated with decreased plasma tryptophan.
PMID: 11336160

Fructose- and sorbitol-reduced diet improves mood and gastrointestinal disturbances in fructose malabsorbers.
PMID: 11099057

Dietary carbohydrates: effects on self-selection, plasma glucose and insulin, and brain indoleaminergic systems in rat.
PMID: 7537031

Lactose malabsorption is associated with early signs of mental depression in females: a preliminary report.
PMID: 9824144

Kallikrein and serotonin in the blood of patients with lactose intolerance
PMID: 4407879

Fructose malabsorption is associated with early signs of mental depression.
PMID: 9620891

Dietary influences on neurotransmission.
PMID: 3026151

Alpha-lactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat.
PMID: 14684242

Effect of different tryptophan sources on amino acids availability to the brain and mood in healthy volunteers. PMID: 18648776

Effects of alpha-lactalbumin on emotional processing in healthy women.
PMID: 17446205

Diet rich in alpha-lactalbumin improves memory in unmedicated recovered depressed patients and matched controls.
PMID: 16174675

wrote on Feb 20^th, 2009 at 3:18pm:

Monty, you need to go back and read about neurotransmitters and synaptic transmittions again because what you said there is not quite correct. SSRIs does affect the level of serotonin AVAILABLE at the synapses of ALL of the nerves which use serotonin as a neurotransmitter.

Ok, lets say that SSRIs work at every single type of nerve anywhere in the body that has serotonin (this isn't true-see below, but lets just say it is true). SSRIs only increase serotonin locally in those spots.

SSRIs do not change the amount of serotonin in the body much (if at all); they make nerve cells more sensitive to it, they increase the effective concentration of it in the synaptic cleft only.  This does not increase the amount of serotonin available for non-neuronal use, or for conversion to melatonin. The MAO inhibitors actually increase blood levels of serotonin,  as do the precursors and the IDO inhibitors. That is an importance difference.

So I don't think we can extrapolate the fact that SSRIs don't seem to do much for clusters to the idea that raising serotonin levels can't possibly be good for clusters, as SSRIs don't really raise total free serotonin. SSRIs are one particular, limited way of changing serotonin activity.




Quote:

The small numbers of serotonergic central neurons of vertebrates and invertebrates produce their effects by use of two modes of secretion: from synaptic terminals, acting locally in hard wired circuits, and from extrasynaptic axonal and somatodendritic release sites in the absence of postsynaptic targets, producing paracrine effects. START PRINTPAGEMultimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or END PRINTPAGE

The SSRIs do not amplify the effects of serotonin in the second type of receptor. Serotonin is both a neurotransmitter, paracrine hormone, and precursor of melatonin and other things.  SSRIs only affect serotonin levels in the synaptic terminals or clefts.

Hi Monty,

Thank you very much for the articles on lactose/fructose intolerance, I will read up on them.  :)

Regarding the second article, it discussed the role of serotonin in general in application to vertebrates and invertebrates' behaviours, more specifically leech. I am talking about the finding of the effects of SSRIs in human.

Anyway, I think we are getting a bit side tracked. The original posts discuss the hypothesis that by modifying serotonin, via diet changes, that we might see an improvement in CH. My point is from what I have learnt about the mechanisms possibly involved in the genesis of CH, it is not the central point. I believe that the key point is the control pathways via feedback system by which the hypothamalamus and the pineal gland maintaining homeostasis for the body. CH seems to be the byproduct of the break down of such. I feel that the key to unravel how and where and why the break down occurs is the functions of the autonomic nervous system, and therefore the "cure" most possibly lies here.

So far, the only chemicals that seem to have the power to completely halt CH in its track are those that have a profound effects on the autonomic nervous system, namely ergotamine and its derivatives.

wrote on Feb 20^th, 2009 at 9:49pm:

Anyway, I think we are getting a bit side tracked

Do not know how I liked reading this. That's what I was looking.


wrote on Feb 20^th, 2009 at 9:49pm:

The original posts discuss the hypothesis that by modifying serotonin, via diet changes, that we might see an improvement in CH

No, no. The original hypothesis has the diet, if that becomes available to discuss it, as a fraction of a more comprehensive plan of action. I just start with it in the next message.


wrote on Feb 20^th, 2009 at 9:49pm:

My point is from what I have learnt about the mechanisms possibly involved in the genesis of CH, it is not the central point. I believe that the key point is the control pathways via feedback system by which the hypothamalamus and the pineal gland maintaining homeostasis for the body. CH seems to be the byproduct of the break down of such. I feel that the key to unravel how and where and why the break down occurs is the functions of the autonomic nervous system, and therefore the "cure" most possibly lies here.

Naturally there may be an indefinite number of hypotheses on the CH. But I have explained one, and hypotheses assumptions should not be demonstrated, so they are called hypotheses, they are accepted 'a priori' and they are discussed to find where they lead. I think it would be interesting to develop your hypothese at other topic in parallel, so that people could participate in this one and/or others, it will always be very interesting for all us.

Regards.

Well, let's get organized and we are in order. I proposed three points relating to the possible increase of serotonin, as I said in the conclusions (2) of my first post of the approach hypothesis. The three points are:

a) Increase the availability of tryptophan
b) Avoid the path of conversion of tryptophan quinurenina
c) To facilitate the conversion of tryptophan to serotonin

With your permission, I would like to initiate discussion on item (a).

Years ago, this was my starting point in my studies and I do not remember in detail all aspects related to this issue, so I write what I remember, I would incur in a multitude of mistakes and I would appreciate your corrections.

Necessarily ingested tryptophan in the diet, that's a fact. Most of the tryptophan consumed remains in the intestine, but a small fraction is able to pass to the blood flow (tryptophan-free call) and a part of it can enter the brain.

Recall that the brain serotonin must to be produced in the brain itself, since it does not cross the blood-brain barrier, so it is vital that tryptophan reaches the brain. To do this, it need a transport, but to gain such transport it must compete with other amino acids "neutral" who have greater capacity to transport than him (tyrosine, phenylalanine, leucine, isoleucine and valine)

Although the pineal gland is outside the blood-brain berrera, it captures only tryptophan combined with albumin against the blood circulation, so the transport remains essential. At least two chemicals help tryptophan to join transport over the other amino acids: insulin and carbohydrate.

Nor should we forget that an excess of tryptophan automatically produces an elevation of T-pirrolasa leading tryptophan to the quinurenina, and since this is a self-regulatory body, does not seem much less desirable exceeding consumption. A normal diet (Western) provides more than enough tryptophan to meet the needs of the organism.

With all that, I theorize some mechanisms to increase the general availability of free tryptophan and brain

1) Do not ingest external tryptophan, at least not in high doses, the effect would be contrary to that sought. When the ingestion of Tryptophan is prescribed, it start at high doses, which decreases over time and stages of abstinence in order to avoid this possible effect.
2) Improve the diet for the tryptophan ingested substances is accompanied by to help you reach the brain, eat something sweet and / or carbohydrate (potatoes, bread, ..)
3) Check that the tryptophan is not eated with a large number of amino acid competitors. In this sense, red meat (cow, pig, etc.). have a lot of tryptophan, but also large amounts of other amino acids. Foods that have tryptophan with less competitors and even transport facilitators are: bananas, turkey meat, whole grains, milk and eggs.
4) Make the ingestion of these foods preferably separated from other ingestions.

Recalling that the excess is counterproductive, and that the availability of brain tryptophan occurs in one or two hours after ingestion, I propose as a first good idea to eat some turkey meat and potatoes, or a turkey sandwich with whole grain cereals, or a banana for dessert. Any of these things looking to do a couple of hours before the scheduled time for the crisis.

Probably, this is not the way to get a significant improvement, much less, but could be a condition “sine qua non" for the points b) and c) can be met.

I do not forget the possible ingestion of 5-HTTP or other issues, but I prefer to concentrate on this first point the mere availability of tryptophan.

I look forward to corrections, comments or ideas.

Wow.  I struggled to get through college chem.  And I spent too much time in biology focused on my lab partner's (and she on mine).

I really appreciate that this discussion is going on.  Please keep up the good work!

      I dont beleive diet can improve CH, Wouldnt this thought have something in line with how we draw "triggers" from certain foods Some people eat candy bar and get CH, Same as smells draw CH.

       Im not understanding the differance of sertonin, and free sertonin, I believe it is in the transmission, and the sertonin and the mushroom chem break down are almost exatlly the same. I know im not that smart and i dont really understand all this but here it is.

     I never got a cycle that started any other time but in the fall, Always after the time change. So something in the brain is sending out cells that lack sertonin and on path back up if they dont have the proper sertonin.. CH.  This is where the mushroom chem breakdown comes into play and fools returning cell into beleive that it is corrected, Because the cem make-up is almost identical.

   So if you can trick the brain with the LSD on returning cells, So dont that mean the problem starts in the cemical make-up of the cells themselfs. I hope this dont sound stupid.


                                Challening, More assertive.. Coach Bill  >:(

coach_bill wrote on Feb 21^st, 2009 at 3:13pm:

I dont beleive diet can improve CH

Nor do I believe that a diet may improve CH, especially because, as I said, a normal Western diet provides more than enough tryptophan to meet our needs. If I touched the subject, it was due to three reasons: first, because it is logical to do the study fairly complete, second, because although a vast majority of us do not have any problem at that level, there is always someone that can have, and thirdly, because it is shown that an adequate intake of tryptophan produces really immediate rises in the levels of serotonin (talking about one/two hours), so in an emergency, some of the things I mention could hopefully raise levels, not to avoid crisis, but making it more bearable. I do not tire of repeating that all these things work hours to view, not days, so they can be useful used just before the crisis, not as daily therapy.


coach_bill wrote on Feb 21^st, 2009 at 3:13pm:

Im not understanding the differance of sertonin, and free sertonin

In simple terms, 90% of serotonin is synthesized in the intestine, and there it is. From the remaining 10%, 8% is captured, stored and transported, particularly by platelets. The rest is free for use by neurons. If the binding potential of transport increases, such in autumn and winter, is rest less free serotonin because it’s captured by platelets. SSRI’s have so much affinity for the transport of serotonin and occupy their site by removing it from these receptors and allowing more free serotonin.


coach_bill wrote on Feb 21^st, 2009 at 3:13pm:

I never got a cycle that started any other time but in the fall, Always after the time change. So something in the brain is sending out cells that lack sertonin and on path back up if they dont have the proper sertonin.. CH.  This is where the mushroom chem breakdown comes into play and fools returning cell into beleive that it is corrected, Because the cem make-up is almost identical. So if you can trick the brain with the LSD on returning cells, So dont that mean the problem starts in the cemical make-up of the cells themselfs

The human being is subjected to a genetic system to 50,000 years old. Only 3,000 years ago we learned to plant, grow and raise livestock, and only a hundred years ago this food is packaged and transported. It has nothing to do our current food with the diet 30,000 years ago. And not only for what we eat, but by the quality, methods of preparation, etc ... Should we take for granted that our body still has not adapted to our new way of life, or our stimuli, or almost nothing. Therefore it is very difficult to find a direct cause of how chemicals affect CH, or anything else, perhaps because they are not direct but indirect and complex because of all these important changes. I also believe that problem is not in the cells themselves but in the circumstances that the body promotes at different seasons (that it want us to do, hibernating, migrating, or changing dietary habits, or God knows what he wants) and it no longer makes sense to us and, of course, we do not.

Regards.

Mechanism of action of drugs.

To not reject a hypothesis, it should at least explain the common observed facts. So little by little I’ll try to present a minimal explanation of how the various drugs that are prescribed for the CH operate.

Ergotamine.

Ergotamin does not deserve much discussion. Its action is predominantly vasoconstrictive, and very powerful. So much so, that combined with other vasoconstricting as triptans, may be fatal.

Ergotamin causes significant vasoconstriction throughout the body, so it would be classified in my first group of hypotheses, the idea of preventing inflammation of the nerve.

I must say that I have consulted some doctors that asked surprised if it’s still prescribed today. The first option seems to be the triptans, the ergot is full of contra-indications, warnings, etc. ..

As a general warning, in addition to substances that are contraindicated with ergot, a leaflet that lacks information: cocaine. Powerful vasoconstrictor, has already resulted in limb amputations in patients due to lack of blood flow. Remember: if you take ergotamine, do not to consume cocaine.

I’ll gradually try to address all drugs and substances as well known by us. Of course, some help would be welcome  :)

Gonzalo wrote on Feb 21^st, 2009 at 12:14am:

3) Check that the tryptophan is not eated with a large number of amino acid competitors. In this sense, red meat (cow, pig, etc.). have a lot of tryptophan, but also large amounts of other amino acids. Foods that have tryptophan with less competitors and even transport facilitators are: bananas, turkey meat, whole grains, milk and eggs.

Ok - some better foods include sesame seed and sunflower seed, if we look at the percent of Tryptophan as compared to the amount of Large Neutral Amino Acids (LNAA).  The LNAA compete with each other for transport into the brain, and include Tryptophan, Isoleucine, Leucine, Valine and Tyrosine.

According to my calculations (time limited, will do more later), these foods have the following % of Tryptophan compared to total LNAA (higher is better):

Sesame seed flour: 9.17
Sunflower seed: 6.79
Banana: 5.57
Coconut water: 5.12
Turkey breast: 4.81

One thing to consider is that sesame and sunflower and coconut are also high in the arginine:lysine ratio, so it may increase nitric oxide levels. I don't know if that would trigger the way that nitrogylcerine does, probably not, but it is possible.  I have had low hdl in the past, and arginine is generally good for increasing hdl and reducing heart risk factors. So I try to drink coconut water and eat sunflower seeds and tahini sesame paste more often. But if I went into cycle, I would have to consider if it might be good to temporarily reduce arginine levels. (Low niacin is also associated with low hdl, and niacin supplements are a good way to increase hdl).

I got the amino acid profiles from START PRINTPAGEMultimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or END PRINTPAGE - they have tables that are mostly from the US Dept of Agriculture.

Ok, a longer list of tryptophan as a percent of LNAA:

Sesame seed flour,  9.17
Wheat flour, whole grain, 7.94
Potato, baked, flesh and skin, 7.48
Cocoa powder, unsweetened, 7.05
Quinoa, uncooked, 7.04
Wheat flour, white, 13% protein, 6.99
Oyster mushroom, raw, 6.96
Tofu, made with nigari, 6.92
Amaranth grain, uncooked, 6.82
Sunflower seeds, 6.79
Whey milk protein, sweet, dried, 6.46
Pumpkin seed (pepitas), 6.37
Shrimp, mixed species, cooked moist heat, 6.25
Soybeans, mature seeds, boiled, 6.25
Pistachio nuts, roasted, salted,  6.23
Peanut butter, smooth, no salt, 5.78
Banana, 5.57
Rice, brown, long grained, cooked, 5.49
Chicken, broilers or fryers, breast, stewed, 5.25
Lamb, trimmed retail cuts, cooked, 5.18
Coconut water, 5.12
Dates, Medjool, 5.12  
Egg, whole, omlet,  5.08
Cod, broiled, 5.01
Salmon, broiled, 5.01
Beans, baked, canned, plain, 4.81
Turkey Breast, 4.81
Milk, skim, 4.73
Bologna, Pork, 4.66
Corn flour, whole grain yellow, 2.75
Ground Beef, 80% lean, 2.26
Yogurt, plain, skim milk,      1.9

Thoughts:  

1) Don't eat crunchy beef tacos!  Corn and beef are very low in tryptophan compared to other LNAAs, and a diet heavy in either of these could reduce the amount of serotonin that can formed in the brain. Lamb is a better red meat with respect to tryptophan (and in many other ways, IMO).

2) Turkey is over-rated when it comes to tryptophan. It is equal to baked beans, less than chicken and many other foods. Actually calculating which foods have the best ratio gives a rather different list than is spread in the urban legends and oral traditions.  I have long said that the Thanksgiving drowsiness is due to eating way too much, not to the amount of tryptophan in turkey. I have taken a large dose of pure tryptophan on an empty stomach, and it has never made me feel like I feel after stuffing myself on Thanksgiving day.

3) A desert dessert concoction of dates, sesame paste, pistachios, sunflower seeds, and maybe a little chocolate and honey could be good - Halva is pretty popular across the Mediterranean ... it is based on ground sesame seeds, and sometimes contains some of the other things I mentioned.  Dates have a good ratio of tryptophan, but the total amount is low ... but they are sweet and tasty, so could be a good mix.

4) Wheat is better than rice, whole wheat is better than white refined wheat. All of these are better than most meats if the goal is to raise brain tryptophan/serotonin.

5) Milk is not that great of a source of tryptophan, but one particular protein in milk (alpha-lactalbumin) is much better. Some of the research on the effects of diet and neurotransmitters uses a purified form of this protein. So far, I haven't found a supplement that is pure alpha-lactalbumin, except when buying in huge volume (1000 kg dried). Whey protein (which is used by many in bodybuilding) is better than normal milk. Yogurt may be good for many reasons, but tryptophan is not one of them.

Foods that are high in protein can overwhelm those that are are medium or low protein. For example, combining four ounces of beef with 4 ounces of wheat bread would not be the average of the two... not ((7.94+2.26)/2) or 5.1.  Since the meat has about 3 -4 times more protein than bread per ounce, the true weighted average for a hamburger would be down around 3.4 to 3.7, which is still quite low. A quarter pounder lambburger would weigh in around 5.8, which is considerably better.  

A stir-fry dish with shrimp, tofu, wheat noodles and a good dash of ground sesame would be above 7 -- twice as much brain-available tryptophan as a hamburger.  

More reasonable over the long term - if someone's diet had a weighted average of 4-5, and they raised it to a 6, that could translate to a 20% to 50% increase in the tryptophan available to the brain. I've run some sample diets, and think that a 20-25% increase is possible without banning or prohibiting any foods, simply eating less of the foods on the low end, more on the high end.

This could actually be done consuming the same amount of tryptophan, so I don't think the enzymes to degrade tryptophan would go up, unless they are controlled by the balance of LNAA instead of the amount of tryptophan.

Because the mechanism for transporting LNAA to the brain is relatively slow and gets saturated, the timing of the food may be important as Gonazalo previously said. Eating foods with a high score first (morning meal, pre-meal (soup/salad) and snacks/empty stomach) could make a difference.

First of all, nice job Golanzo, I don't think your translation was awful at all. I understood it pretty well.

Second, there's a thread on here titled Why don't we pay attention to this? It's referring specifically to how testosterone imbalance can effect CH. You might want to read it... I don't know if testosterone has any effect on serotonin, but it might be something to look at.

I can't remember if there are any other threads mentioning other forms of imbalances, at the moment...


monty wrote on Feb 18^th, 2009 at 10:58am:

Ok - a few other possible therapies. At least 2 probiotic bacteria (Bifidobacterium adolescentis and Bifidobacterium longum) reduce tryptophan pyrrolase activity in the gut. Shiitake mushroom stimulates Bifidobacteria breve and Lactobacillus brevis, and leads to reduced levels of tryptophanase in the gut. PMID: 18982487 Curcumin (turmeric) decreases conversion of serotonin to 5-HIAA (MAO inhibitor?) Curcumin also has beneficial effects on the balance of 5-ht1 and 5-ht2 receptors (stimulates -1 and inhibits -2). For a variety of other reasons, curcumin seems like a potential good treatment. Am working on a longer write-up of curcumin, but will throw it out here. "Excessive doses of retinol (vitamin A) reduces liver t-pyrrolase ... not sure how toxic these 'excessive' levels are.  PMID 17942093. Will keep sifting through the list to see what else might be significant.

Random Fact! High amounts of vitamin A also can cause increased intracranial hypertension. (I had this, though, not due to getting too much vitamin A.) Avoid eating polar bear livers. ;)

PFDAN

Mystina

No doubt, vitamin A can be toxic at certain doses. I am wondering what the original article meant by 'excessive' - it could be that anything over 100% of the daily allowance might be considered excessive. Doubling or tripling or quadrupling that for a short time would have little toxicity, not sure if that would be enough to reduce the tryptophanase activity for a cycle.

I think a diet limited to polar bear liver has 100,000x the daily allowance - that gets toxic quick.

Monty and Gonzalo,

From your own personal experience, have you found/noticed significant improvement of your CH when consuming tryptophan rich food ?

If you have, is there a particular combination/list of food that you found to be reliably effective ? What is the time frame you recommend  for such diet change ?

Thanks for sharing.

I have been in remission for a while, and have only been recently researching this aspect of the food strategy for raising tryptophan/serotonin.

I have experienced improvement of CH symptoms from 5-htp, an amino acid derivative that is a serotonin precursor. Others have tried it, some seem to benefit, others report an increase in hits from it. There are also studies on the benefits of 5-htp and migraine, particularly migraine with aura (which I also get from time to time). Whether or not that can be extrapolated to CH or not, I don't know ... maybe a subset of people with CH.  

Up until 2004, I had an undiagnosed/misdiagnosed fructose intolerance. Since I have corrected my diet to account for that, I have seen a big improvement in depressive symptoms, and have been in remission for CH. (I do not claim to know why I am in remission - improving tryptophan could be a factor, or maybe it is a coincidence. There were other changes at that time, including a change of jobs that led to better sleep hygeine.)

I found out about the fructose intolerance sorta by accident - my panic attacks (which were daily) turned off on day 2 of a low-carb diet. Over time, I lost some weight, felt better, and started re-introducing carbs to my diet ... eventually the day came to splurge on a cola, and the GI distress that someone called IBS came back immediately, and the panic started a few hours later. Abstaining led to normalcy, challenges with soft drinks or large amounts of fruit led to a return of the GI and nervous system symptoms.

Bottom line opinion - I think some people might see CH benefits from dietary improvement of tryptophan availability, but it is still speculative. The literature on diet, tryptophan and mood suggest a benefit for some common co-morbities like anxiety and depression. I think if it is combined with other things (changes in microbial ecology for less tryptophanase and reduced neuroimmune activation, inhibition of IDO in the brain, enhancing 5ht1 while inhibiting 5ht2, changes in light exposure, etc), then maybe it could be good for some of us. But not sure yet.

Note also, while there are many people that believe that 5-htp helps migraine (and articles to support this), the consensus seems to be that SSRIs don't do much for migraine.  Whether or not this transfers over to clusters, I don't know. But it does lend some support to previous ideas that SSRIs are somewhat different than raising serotonin everywhere.  

Hello, Pixie-Elf

Second, there's a thread on here titled Why don't we pay attention to this? It's referring specifically to how testosterone imbalance can effect CH. You might want to read it... I don't know if testosterone has any effect on serotonin, but it might be something to look at.

Absolutely, I have already taked a look. Time ago I was seeing and reading about this and many other neurotransmitters and hormones. But for now I agree that we can agree on specific issues relating to this hypothese and I sincerely believe that the next step would be to study the relationship between the sympathetic and parasympathetic system, and there is also growth hormone (HGH), which seems to me that is more involved than any other in our processes. There will be time for everything ...

With regard to vitamin A, or any other substance to be used outside of the thresholds tested and safe, I did not consider. I will live with this forty years and all my struggle is precisely not to consume drugs or unhealthy substances, as far as possible. Although it may seem incredible, and even stupid, I've never taken any medicine prescribed for the CH.

Monty, your meal post is wonderful. It's difficult to translate food diets and names from continent to continent, but we will. And I think this issue is close to short, write and follow road. And I propose that the following is the path of kynurenina, ie how to avoid it. Hence in principle we have just two elements: the 2.3-tryptophan dihidroxigenasa (T-pirrolasa) and indolamina 2.3-dihidrooxigenasa. And the rebound B3. When you want..., or if you prefer to start by way of serotonin, as desired.

Annsie, hello.

Yes I've tried the diet, in fact, this was the really first thing I tried with CH. I noticed that the improvements were quite minimal, in fact, just to verify that the CH was not untouchable and I take illusion to learn more. The next thing I tried was vitamins and there, yes, you feel that much, then, after, I tried vitamins with and without  diet, and no difference noted, I forgot about the diet. And never do it now.

I will insist that I think it is okay to set some basic data on this, and to be followed a few days just to make sure that the normal diet was valid. I know about some people that use diet with very good results, but all of them combined with a host of other products, making it impossible to make assessments.

Finally, there is no question of changing the diet. The idea, in my view, one thing is to try to provide an improved tryptophan couple of hours before the crisis and see if there is a result or not. I have my crisis at night and tooked a steak turkey dinner with a dessert banana for a few days for testing. Just that.

But more important than make a "good " diet is to know how evitate to make a "bad" diet.

Regards.

Summary of Assumptions

This scheme will serve as a benchmark for the discussion and must be completed as various items contained are discussed.

Bases of the hypothesis

   1) The trigeminal nerve is extremely sensitive in patients with CH and ignites more easily from the normal.
   2) The levels of serotonin are crucial for controlling the cycles of crisis and the need for action on its specific receptors responsible for vasoconstriction in the cranial vessels.

Actions based on theoretical assumptions

1) Prevent or reduce inflammation

    A) To improve the overall fitness of the nerve
    B) Avoid physical damage to the nerve
    C) To avoid an excessive and continuous expansion of the cranial vessels
    D) To promote the constriction of cranial vessels

2) Increasing the production of serotonin

    A) Increase the availability of the precursor tryptophan
    B) Reduce the metabolism of tryptophan to different pathways than the serotonin pathway.
    C) Improving the production of serotonin improving it pathway of tryptophan metabolites

3) To reduce losses or decreases in serotonin

    A) Outstanding (MAOI ?...)

4) Avoid storage of serotonin increasing free serotonin

    A) Outstanding (SSRI's ....)

5) Improve the effectiveness of serotonin available

    A) Outstanding (receivers ...)

I'm not inclined to be medically-minded and so am still stuck back here, basically your first post.


Gonzalo wrote on Feb 24^th, 2009 at 1:28am:

1) The trigeminal nerve is extremely sensitive in patients with CH and ignites more easily from the normal.

This seems like a strange occurence.  Is there any other one-sidedness sensitivity that evolves like clusters in another medical condition?  Why does this seem so original?



Quote:

The determination of whether damage is due to friction with the bone structure, damage or sensitivity of the neurons themselves, or any other cause, is outside of this dissertation.

I realize this has been skipped for now, but this cause is elusive still.



Quote:

However, it is public knowledge that a patient may suffer a CR of a sudden crisis, or even start a cycle, by a direct action on the trigeminal nerve or its branches. Examples include oral infections, extractions mouth parts, the mere application of a pre-anesthesia tronculares manipulation, otitis and even trauma. If a direct action on the trigeminal nerve can cause a crisis immediately, without any intervention by neurochemical processes, we must conclude that the trigeminal nerve is damaged in some way.

I'm not so aware of the public knowledge mentioned, more familiar with a cyclical nature, and can understand an artery up there as a direct action creating the second circumstance.  While both perplexing, does this one-sided trigeminal damage, sensitivity, have a precendent?  The fact it occurs on the same side as the cranial vessel's direct action would make it seem a conjunctive mechanism at work, as opposed to separate.  This would be accepting the damaged nerve portion of basis.



Quote:

...thus creating a feedback system during the crisis.

To mention, I cut this sentence to only the part that raised an eyebrow of previously suspected agreeability, without quite understanding more.  

Kevin_M wrote on Feb 24^th, 2009 at 6:29am:

I'm not inclined to be medically-minded and so am still stuck back here, basically your first post. Gonzalo wrote on Feb 24th, 2009 at 1:28am: 1) The trigeminal nerve is extremely sensitive in patients with CH and ignites more easily from the normal. This seems like a strange occurence.  Is there any other one-sidedness sensitivity that evolves like clusters in another medical condition?  Why does this seem so original?

Gonzalo, I agree with Kevin.

My biggest problem with your hypothesis is that if what you said above is true, then all CHers should have symptoms of trigeminal neuralgia, but we dont.

One of the most striking feature of trigeminal neuralgia is the severe pain caused by chewing, while in CH the pain is only present and severe during a hit. Outside a hit, a CHer can chew without feeling pain.

It doesnt seem that in CHers, the trigeminal nerve is extremely sensitive nor damaged.

Hello, Kevin_M, Annsie

I feel I must clarify what is a clear misunderstanding. To do this, I quote the definition of the word hypothesis, according to the Royal Academy of Spanish, and an approximate translation, as well as othe definition that I found in English.

"Hipótesis: suposición de algo posible o imposible para sacar de ello una consecuencia" (Assuming something possible or impossible to get a result of this)

"A tentative assumption made in order to draw out and test its logical or empirical consequences"

The hypothesis may be false, unreal and improbable or even impossible. Can hypothesize that one imagine anything. What is important is the discussion it caused. This discussion may seem absurd to anyone, useless, interesting, or anything else, and during it we can do all sorts of allegations, all that is therein; discuss everything … everything but the validity of the hypothesis which is out of the discussion, it’s the starting point of the discussion.

If I could justify all that’s said in the approach of the hypothesis, then it would not be a scenario, I would be stating a theory, but it is not.

I raised this way just to skip this, the eternal discussion of the primary cause of CH, still discussed by doctors and scientists to fully enter into the discussion of the serotonin pathways, which is a subject that at a practical level I believe can be helpful.

Regards.

Quote:

My biggest problem with your hypothesis is that if what you said above is true, then all CHers should have symptoms of trigeminal neuralgia, but we dont.

CH has been classified as a type of trigeminal neuralgia - intermittent, to be sure, of a different frequency than classic trigeminal neuralgia, but a case where there is undoubtedly trigeminal nerve pain.

The trigeminal is getting inputs from the brain,and from peripheral areas. It processes those inputs, and then fires when the threshold is reached.

I think that was distinguishes CH from classical TN is that the hypothalamus is the strongest driver in clusters, while peripheral is more important in classic TN. In classic TN, triggers include brushing the hair, touching the face, yawning.

But peripheral input could be a factor in CH- allergies, rhinovirus infections, TMJ jaw issues, neuromuscular lesions, etc are all suspect in some people.

The trigeminal could be damaged and still function adequately under normal circumstances. It only becomes obviously dysfunctional when 'stress' hits a certain level.

Gonzalo wrote on Feb 24^th, 2009 at 2:21pm:

Hello, Kevin_M, Annsie I feel I must clarify what is a clear misunderstanding. ... The hypothesis may be false, unreal and improbable or even impossible.  ..... ; discuss everything … everything but the validity of the hypothesis which is out of the discussion, it’s the starting point of the discussion. Regards.

Thats not how a hypothesis is presented Gonzalo.

A hypothesis needs to have some solid base from which it can be defended. A hypothesis can be proven correct or incorrect after a long and thorough discussion and examination, but it can also be thrown out relatively quickly if it is not based on something fundamentally sound, at least partially.

The validity of a hypothesis needs to be established first before any subsequent discussion can make sense. Whats the point of discussing something that is not even valid ?

I am not saying that your hypothesis is invalid at this stage, I am just pointing out the big hole that it has in its fundamental fabrication.

monty wrote on Feb 24^th, 2009 at 2:55pm:

Quote: My biggest problem with your hypothesis is that if what you said above is true, then all CHers should have symptoms of trigeminal neuralgia, but we dont. CH has been classified as a type of trigeminal neuralgia - intermittent, to be sure, of a different frequency than classic trigeminal neuralgia, but a case where there is undoubtedly trigeminal nerve pain. The trigeminal is getting inputs from the brain,and from peripheral areas. It processes those inputs, and then fires when the threshold is reached. I think that was distinguishes CH from classical TN is that the hypothalamus is the strongest driver in clusters, while peripheral is more important in classic TN. In classic TN, triggers include brushing the hair, touching the face, yawning. But peripheral input could be a factor in CH- allergies, rhinovirus infections, TMJ jaw issues, neuromuscular lesions, etc are all suspect in some people. The trigeminal could be damaged and still function adequately under normal circumstances. It only becomes obviously dysfunctional when 'stress' hits a certain level.

You are missing the point here Flo. I am not saying that CH does not have trigeminal neuralgic pain. What I am saying is that CH does not have symptoms of a damaged trigeminal nerve. It is the hypothalamus that is malfunctioning not the trigeminal nerve.

Gonzalo's hypothesis "requires" the trigeminal nerve to be damaged and therefore extra sensitive to any and all signals.

I am saying that in CH the trigeminal does not have to be damaged at all but can still fire abnormal signals because its control centre is off.

Gonzalo's hypothesis focusses on the trigeminal nerve as the centre of action in CH and he speculates that by " supporting " a damaged and oversensitive TN with various varying factors will help CH.

I on the other hand says that the TN is only a small player in the picture of CH. It is the pineal gland and the hypothalamus we should focus on. If those 2 glands are malfunctioning, then no matter how much we "nurture" the TN its going to fire abnormally in a hit.

Proposal of resume for the 2A.

2) Increasing the production of serotonin
   A) Increase the availability of the precursor tryptophan

Tryptophan is an amino acid that must necessarily be consumed in the diet because the body can not synthesize it from other substances. Tryptophan, once absorbed, needs a special mechanism of transport to access the brain, and to use this transportation disadvantaged in competing with other amino acids such as tyrosine, phenylalanine, leucine, isoleucine and valine (LNAAs). Thus, is as relevant the proportion tryptophan / LNNAs as the amount of tryptophan ingested. To improve access to transport for his arrival ingest before a carbohydrate and / or glucose. There is also a mechanism that is activated by an excess of tryptophan that increases its degradation preventing their processing to serotonin.

A Western diet outweigh the covers normal daily requirement of this amino acid, so that the ideal is not necessarily increase the amount of tryptophan, but taken with the low level of competition LNAAs possible, even better yet, away from food, thus be improved not only transportation but also its absorption.

The arrival of tryptophan to the brain may occur when adequately ingested ½ -2 hours, and remains 2 / 3 hours, so it is important to do the intake a couple of hours before the start of the crisis, for it is fully available at the time. Suffice it to take a banana, a small turkey sandwich with whole wheat, or a simple glass of milk, for example, at bedtime, to help lift standards in the first hours of sleep.

Of course, it can also be eaten directly as a dietary supplement. In this case, it remains valid the separation of the foods to avoid competition and improve the absorption and, in case of a long-time intake, the use of a protocol to start with higher doses, it decreased gradually and without any periodos free of intake to avoid the self-regulatory mechanisms.

More info and thoughts for meals in the post link **(to Monty post about)**

*****************
It's needed a clear disclaimer that left clear that this are just theoretical ideas from sufferers, not doc by doctors.

Now,
what's wrong?
what I missed?
what is in more?
It's clear or so technical?

and ...  :-[ after all that it will need an important tranlation clean I can't do....

wrote on Feb 24^th, 2009 at 3:57pm:

I on the other hand says that the TN is only a small player in the picture of CH. It is the pineal gland and the hypothalamus we should focus on. If those 2 glands are malfunctioning, then no matter how much we "nurture" the TN its going to fire abnormally in a hit.

That is a common perspective and there are many researchers focused on the hypothalamus.  I don't deny the importance of the hypothalamus, but think that the trigeminal itself is important. Reasons include:

1) Non-Hypothalamic cluster headache documented by Rozen.
2) Phantom clusters - all the autonomic symptoms, no pain from trigeminal.
3) Research that suggests that problems with trigeminal may be common in CH, and that improvement is seen if possible to treat trigeminal lesions.
4) Nerve blocks - they don't involve injections to the hypothalamus.
5) Myofascial therapy can be an effective treatment.
6) Association of clusters with sinus issues, TMJ jaw problems.
7) Immunology - trigeminal nerve more likely to be affected than hypothalamus by epstein-barr virus or other viruses that are more common in CH.

1) Rozen's work on this is preliminary, but worth considering, even if it is a minority of cases.

2) I have experienced phantom clusters, and I believe it is the hypothalamus going haywire, but the trigeminal does not respond by releasing pain inducing substances. If this is true, then it offers treatment options for the pain - not a complete therapy, but less excruciating agony.

3) See START PRINTPAGEMultimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or END PRINTPAGE

4) Nerve blocks reduce peripheral inputs to other areas; the most effective is a sphenopalatine, which is part of the trigeminal nerve.

5) Myofascial therapy - recently show to help with CH. A reduction of peripheral inputs to trigeminal from muscles in head makes the most sense, the hypothalamus is not directly affected by such procedures, but the trigeminal is.

6) A ten year follow-up study on endonasal surgery for clusters found about 1/3 of patients who got surgery went into remission and were there for ten years, about 1/3 displayed marked improvement. The hypothalamus-centered theory cannot explain this. Not everyone with clusters has such contact points, but those who do seem to benefit benefit from treating them. Other related problems include chronic sinusitis, tmj ... my impression is that they are more common in CH, although there is not a lot of data on that.

So I am not trying to erase the role of the pineal and hypothalamus - they are important and clearly contribute. That is a very good explanation of the timing that many of us have for headaches. The hypothalamus is a source of input to the trigeminal that can make it scream.  But I think the immediate source of the pain is the trigeminal behind the eye, and this is important. Sometimes the trigeminal can scream bloody cluster even when the hypothalamus is quiet, and sometimes the hypothalamus is hitting the trigeminal full blast, but the trigeminal does not scream.

Gonzalo,

I think 2A is pretty good. I am assuming 2A is mostly diet related.

For 2B, there is IDO (indoleamine 2,3 dioxygenase) that can be blocked in the body, and bacterial tryptophanase that can be blocked in the gut.

IDO blockers:

Herbal
Propolis
Curcumin (turmeric/curry and extracts)
Rosmarinic Acid (lemon balm, rosemary)
(-)-Epigallocatechin gallate (green tea)
p-Coumaric acid (various herbs)
brassinin (broccoli, cabbage, related plants)


Prescription and experimental
Minocycline
Levo-1-methyl tryptophan
pyrrolidine dithiocarbamate (PDTC) ('antioxidant')
2-ME ('antioxidant')
ebselen ('antioxidant')
t-butyl hydroquinone ('antioxidant')



Things that increase IDO:
Interferon
Influenza
Toxoplasma infection
LPS (lip-poly-saccharide) from some bacteria
inflammation (?)
estrogen


Bacterial tryptophanase blocking:

Probiotic bacteria

Hey, Monty

Indeed, the 2A is only diet, and focused only on the availability of tryptophan, because the diet should be reviewed to other substances that may be beneficial or harmful in other ways.

you entered 2B, I was somewhat prepared 2C, so I let it posted and so we can discuss both at a time; most of the documents we'll read cover two questions together.

2B respect, you let me really surprised, does not have the slightest idea of what's what, but I'll learn. But two important things: first, is that not only is the IDO, also the 2.3-tryptophan dioxygenase (t-pyrrolase), hereinafter TDO, and not just to do the substances that block them ("good"), but those who powers them, too ("bad"). So we have four areas of work with the inhibitors/enhancers of IDO/TDO.

One final point about it: I believe that the path of the bacterial metabolism of tryptophan in the intestine did not affect us, in fact we know that 90% of serotonin is in it. I think we must focus in only the L-Tryptophan absorbed from the intestine to the bloodstream. You'll say.

Because these days I work a lot, I present 2C issue without too much depth, and I hope we will gradually deepen it. And here is:

---

In principle, as I said, the process is:

1) Tryptofhan + enzyme T-tryptophan hydroxylase (TPOH) + cofactor tetrahidrobiopterín => 5-Hydroxytryptophan (5HTP).

2) 5HTP + 5-Hydroxytryptophan decarboxylase + cofactor priridoxal phosphate => serotonin (5HT).

These are the direct factors, but there are many other indirect essential for any cause for the process. They are:

- Vitamin B2 (riboflavin)
- Iron
- Magnesium
- Vitamin C (ascorbic acid)
- Oxygen

I think the tetrahidrobiopterin deficit should not be considered, because its lack causes serious diseases, so it should be guaranteed levels. The rest of actors are:

TPOH.- In the process (1) tryptophan=> 5HTP acts as, and emphasize this many authors, limiting factor. It is in the air how to improve their standards or to prevent their relegation.
5-HTP decarboxylase. - No idea.
Vitamin B6 .- Essential to have pyridoxal phosphate.
Vitamin B2.- Essential to transform B6, pyridoxine phosphate, into pyridoxal phosphate.
Iron, magnesium.- It is said in many reviews, but I have not come to see the mechanism by which they operate.
Vitamin C.- It's said in many reviews, too, but I have not found the mechanism by which they operate. At least it is necessary to get the iron.
Oxygen.- Essential for the oxidation process (1). As I said, I believe that its importance extends to other important issues, as we'll see.

And it rest the possibilty of intake 5-HTP directly ...........

---

And I say something I thought while I was studying this about the 5-HTP intake: it's possible that people whose process (1) is reduced can see CH improved by the 5-HTP intake because finally they have it.
But other people with problems at process (2) due for example, in the absence of B2 and/or B6, were found with excessive levels of 5-HTP, their own plus the intaked, and since 5-HTP is a competitor of serotonin (like melatonin itself and other similar substances) by the same receptors, this would explain that they feel bad, they should have something similar to the symptoms of the hypersertoninérgic syndrome ... it would be nice to check the symptoms of those who have felt bad with 5-HTP.

Finally, if you, Monty (there's someone more ...?) could copy/paste and polish the 2A resume (of course you now I do my best, but that's not enough), I would like to insert it in the "resume". This way, with a link inserted in the first post to it, everybody could easily read latest "conclusions". Do you think it's a good idea?

Best regards

OK.

I read this entire thread.  What I did not understand, I investigated on the 'net.  (some I still did not understand, but........give me time).

One obvious question stood out in my mind..............(I am sure there is a good reason for this..............but I am a newbie)

Increasing serotonin..................no one has mentioned the benefits of exercise to increase serotonin levels.

While I know there is not 100% proof positive that exercise WILL increase serotonin levels, I find there is enough data to facilitate further study.

Personally, I know that my attacks are less frequent, and less severe, when I exercise................energetically................. at least one hour per day.

Perhaps this is just a personal observation, and not based on fact?

Debbie

wagwoman wrote on Feb 28^th, 2009 at 7:24pm:

Personally, I know that my attacks are less frequent, and less severe, when I exercise................energetically................. at least one hour per day. Perhaps this is just a personal observation, and not based on fact?

Hello,

I think it's important to put on the table a formal summary of the data medium, substances and processes that affect serotonin before discussing, and I personally will enjoy doing it, about concrete situations. Such discussions might be to force us to delete or add things, or leave all or part undone.

Particularly with respect to the exercise, I have in mind, and I speak of memory, two contradictory data: the first is that physical exertion produces lack of oxygene, hypoxia, and cortisol is generated and this would produce T-pirrolasa so serotonin will decrease. The second is that if you practice a certain exercise intensity for space exceeding 30 minutes, the body activates a whole system of hormonal secretion, including growth (HGH), which completely alters the state after the exercise. But there must be intense and more than 30 minutes, otherwise there is no such download.

So a simple effort could call the beast, but the exercise seriously, it might scare. Who knows, we need to find and compare information and ideas, but we will get this, or I hope so.

Monty

I am searching and reading everything I get of IDO in Spanish, and I'm reading again and again works on the immune system and cancer, especially bowel. I have it already mania, it seems a bad thing, the IDO. :D

For now, not a single detail of what inhibits or improves its levels, of course you have a prodigious source of information or I am a bit clumsy ... or both. I continue to do so; when I get bored of Spanish will turn to French and I'll comment if I find interesting things.

Regards.

wagwoman wrote on Feb 28^th, 2009 at 7:24pm:

OK. One obvious question stood out in my mind..............(I am sure there is a good reason for this..............but I am a newbie) Increasing serotonin..................no one has mentioned the benefits of exercise to increase serotonin levels. Perhaps this is just a personal observation, and not based on fact? Debbie

Doh!  Exercise is an obvious possibility for raising serotonin levels - thank you for pointing that out.  One problem I have is that I usually get hit in summer and I become much more sensitive to heat and any type of exertion.  But this is one option for some people.


Quote:

Clin Exp Pharmacol Physiol. 2009 Feb;36(2):189-91.   Effect of endurance training on hypothalamic serotonin concentration and performance.    Caperuto EC, dos Santos RV, Mello MT, Costa Rosa LF.    Department of Bioscience, Federal University of São Paulo, Baixada Santista, Brazil.    1. Serotonin is a neurotransmitter that modulates several functions, such as food intake, energy expenditure, motor activity, mood and sleep. Acute exhaustive endurance exercise increases the synthesis, concentration and metabolism of serotonin in the brain. This phenomenon could be responsible for central fatigue after prolonged and exhaustive exercise. However, the effect of chronic exhaustive training on serotonin is not known. The present study was conducted to examine the effect of exhaustive endurance training on performance and serotonin concentrations in the hypothalamus of trained rats. 2. Rats were divided into three groups: sedentary rats (SED), moderately trained rats (MOD) and exhaustively trained rats (EXT), with an increase of 200% in the load carried during the final week of training. 3. Hypothalamic serotonin concentrations were similar between the SED and MOD groups, but were higher in the EXT group (P < 0.05). Performance was lower in the EXT group compared with the MOD group (P < 0.05). 4. Thus, the present study demonstrates that exhaustive training increases serotonin concentrations in the hypothalamus, together with decreased endurance performance after inadequate recovery time. However, the mechanism underlying these changes remains unknown.    PMID: 19220327 [PubMed - in process]

Reading this thread leaves a lot of room for confusion for laymen like myself.

I understand the hypothesis in regards to increase and decrease of serotonin and its pathways. Its a noble effort and appreciated very much.

I think for any of the inputs posted to ultimately make some sense and add inputs from others, there would be a need to back up and attempt to determine what is a normal level of serotonin in humankind if one exists, its usage and variations.
Not sure science itself has moved that far.
Then the discussion of what changes that, could continue and prove more beneficial to a lot of us.

My own observations as well as others may be based more on personal experience and how certain dietary foods can cause those alterations in serotonin usage and pathways.
Those in the know can make some assumptions regarding those inputs, ie: grapefruit and other affecting foods.

The trigeminal nerve and hypothalamus etc.. firings and bypass do appear to be related to serotonin and the previous discourse is indeed beneficial but that need remains to understand why or where normality exists and why modify these inputs whether through dietary or other means.

A lot of benefit can come from random inputs when there are those that can assimilate those inputs into the hypothesis. not easy staying on track.

The larger part of my confusion is related to the why's of increasing serotonin when my experience shows the possible blocking of increased serotonin in certain brain pathways/receptors is beneficial.
I do understand the efforts to explain the fabrication or alteration of serotonin just how its potential benefit exists in our aide has allways escaped me without first finding a benchmark to go by.

MJ wrote on Mar 1^st, 2009 at 2:01pm:

I think for any of the inputs posted to ultimately make some sense and add inputs from others, there would be a need to back up and attempt to determine what is a normal level of serotonin in humankind if one exists, its usage and variations. Not sure science itself has moved that far. Then the discussion of what changes that, could continue and prove more beneficial to a lot of us.

Here is an interesting article I just ran across, "How to increase serotonin in the human brain without drugs" by Simon N. Young:

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It is more about anxiety, aggression and hostility than a process like cluster headaches, but it kinda addresses this question and cites evidence that there is "an association between measures related to serotonin and mood in the normal range."

It focuses on 4 modes of change - cognitive changes, diet, exercise and light exposure.  


MJ wrote on Mar 1^st, 2009 at 2:01pm:

The larger part of my confusion is related to the why's of increasing serotonin when my experience shows the possible blocking of increased serotonin in certain brain pathways/receptors is beneficial.

Yes, that may be a real issue.  There are different serotonin receptors, and they seem to work against each other. It seems that blocking some receptors (2a, 2c) helps, while stimulating the serotonin 1 receptors (like triptans do) is beneficial.

A question I am checking on now is how low levels of tryptophan/serotonin affect the function of the different types of receptors.  It could be that some of us have the wrong balance of receptors due to genetics, exposure to chemicals, injury or disease ... if low tryptophan/serotonin levels can also cause a negative shift, that would be significant.  

One possibility is related to melatonin - low serotonin is 99% guaranteed to lower melatonin.  We know that melatonin is low in most clusterheads, and we know that melatonin helps many of us. So the idea of dealing with this has some interest.  Of course, it is possible that melatonin is low due to some other glitch, and that increasing serotonin will increase melatonin in most people, but not in CH.  

An added thought is that these discussions may ultimately help to understand the variations in CH. Why some folks get as little as 1 0r 2 hits a week and some get hit as many as 10 or more times per 24 hrs.

Hello MJ. I copy/paste mi idea about this isuue from other post.

"The hypothesis can make predictions about the multiple crises. As already mentioned, while suffering a crisis the platelets release serotonin, which acts sooner or later to produce adequate vasoconstriction and abort the process. After the crisis, the platelet re-capture the serotonin they had released, and when it comes back to the previous level, another crisis will begin.

Exacerbated this process by the reduction of serotonin throughout the day, we could theorize that anyone who suffers a crisis in the first hours of maximum levels, at the zenith of the day, must suffer more crises, because the standards of the rest of the day will always be lower . The elapsed time between two crisis is given by the time it takes platelets to re-capture that released serotonin and reduced to the extent that decreases serotonin in the body. Thus, the time between crisis should decrease as the day progresses, and minimum during the night.

Those who have high average levels, will face only a crisis everyday, in the middle of the night, preferably during sleep. Who has the crisis relatively quickly, well before bedtime, would run greater risk of repeating during sleep. Also it is expected that the time of serotonin reuptake by platelets is proportional to the time of release, that is, the duration of the crisis, so longer crisis should be more spaced in time, and shorter, more together in time."


monty wrote on Mar 1^st, 2009 at 2:17pm:

Of course, it is possible that (...) increasing serotonin will increase melatonin in most people, but not in CH.

Is this a mistake? Are you saying that a serotonine raise will not produce a melatonine raise? I understood well? If yes, why do you say this?

Regards.

Gonzalo wrote on Mar 1^st, 2009 at 6:52pm:

Is this a mistake? Are you saying that a serotonine raise will not produce a melatonine raise? I understood well? If yes, why do you say this? Regards.

I am saying we don't know for sure.  In a healthy person, if we deprive them of tryptophan, that will lower serotonin and lower melatonin.  If we then return that person to a healthy diet, serotonin goes up and then melatonin goes up. In that scenario, it is straightforward.

In cluster headaches, it may just as simple, or there may be something more.  We don't know why the melatonin curve for people with cluster headaches is flatter or completely flat, when normal people have a nice peak that corresponds to night and a valley that corresponds to day.  There could be many reasons for this - one is a lack of serotonin, the necessary building block.  But it could be something else - maybe in some people, there is enough serotonin, but there is something else lacking.  Maybe the pineal isn't working properly, maybe there is an endocrine issue (gonadotropin and corticotropin problem).

When I took 5-htp, I felt that I slept much better, so in my case I believe that increasing serotonin did increase melatonin.