Monday 25 November 2013

Sorry Nitric Acid, its not ALL your fault...though I still hate you


In my last post I pointed the finger at Nitric Oxide as being the main culprit for the dreadful, disabling and torturous symptoms experienced during ''protracted withdrawal'' .  On further reading I realize I was unfair to pin all the blame on the one molecule..., NO is what I guess should be called an ACCOMPLICE....It it one of the gang of molecules trying to destroy our brains (and succeeding) but it is not NO alone that causes the damage...

For the massive amounts of severe damage to take place NO must be combined with superoxide to form peroxynitrite and it is the peroxynitrite, a free radical,  that reeks havoc in the brain, causing damage, demyelination, axonal death and the loss of BBB integrity.

Glutamate and Perxoynitrite

For many years, across all psych drug message boards and support groups Glutamate  has been a source of much interest and speculation, some have found taking micro doses of lamictal which can calm the neuronal messaging of Glutamate in the brain, has been helpful...others speak of this issue being an up-regulation of Glutamate receptors after coming off the drugs, and time needed for this imbalance to be corrected...but again, could we be missing a vital piece of information??

Dr GS Scott on his paper, Glutimate - stimulated peroxinitrite production in a brain derived endothelial cell line is dependant on N-Methyl D - aspartate (NMDA) receptors - speaks about the toxic properties of Glutamate in the brain, he gives the example that, ''in the animal model of MS it is demonstrated that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents BBB breakdown'' (1)

But it is not Glutamate itself that is doing the damage, oh no, its ''ONOO''  he states in his paper that ''Glutamate triggers the production of Nitric Oxide and Superoxide, which can lead to the formation of peroxynitrite (ONOO) , we propose that Glutamate contributes to BBB breakdown via the actions of ONOO.'' (1)

There are hundreds of studies also confirming the fact that excess levels of Glutamate cause the cycle of ONOO and cause mass cell damage in the brain...the question remains, what on earth can we do about it??

What Can We Do?

Ahhh, the question that always haunts me, so what can I do to help myself, how can I heal, what steps can I take that are not going to give me a massive set back??

As far as I can see right now there are a few things that need to be addressed

1) dont do anything to make it worse...by not doing anything to make it worse, I think that would include tapering any drugs, introducing new drugs to the bloodstream, taking any suppliments that will increase L-Arginine and keeping away from Oxiditive stress as much as possible.

2) address the BBB destruction - this remains a very difficult conundrum, supplements could help heal the brain and improve health but as our BBB are not working most supplements, substances
and medications prove to at best cause a setback and at worse possibly add to the damage.

Also, once again we are caught in a cycle, ONOO causes damage to the BBB, but our BBB breakdown makes it hard to address the ONOO cycle...I guess its down to taking any ''treatment'' very slowly and monitoring oneself for any worsening as I try to heal myself.

3) address the ONOO cycle - 

By addressing the ONOO cycle, there are 3 prongs of attack

1) Limit or inhibit uptake of Nitric Oxide

2) Limit or inhibit Superoxides

3) Address the high levels of damaging  Peroxynitrite in the brain.

Logic would tell me that addressing the Peroxinitrite itself should be the first line of defense, as its presence is what is causing the damage, NO, and superoxide can be damaging, but put together they form a monolithic monster of epic proportions, this beast has to be taken down first right?

So how do we do that? There is no simple answer but there are ideas...

URIC ACID

Uric Acid is a scavenger of Peroxynitrate, there are studies into the second phase now that show it can be helpful with both parkinsons and MS, Uric acid can be increased using the supplement INOSINE. http://en.wikipedia.org/wiki/Inosine

DC Hooper et al published a study called Uric Acid, a natural scavenger or peroxynitrite, in experimental allergic encephalomyelitis and multiple sclorosis...

In this study he experiments with increasing Uric Acid to mice who have been given poisons and developing the chronic form of  EAE with remissions and exacerbation, he found that ''Uric Acid administration was found to have strong therapeutic effects in a dose dependent fashion'' he further points out this could be because mice, unlike humans have a rapid clearance of uric acid.so humans could require a much lower dose.

He also draws attention to the fact that ''A possible association between MS, the disease on which EAE is modeled and uric acid is supported by the finding that patients with MS have significantly lower levels of serum Uric Acid than Controls.'' (2)

There are also severeal studies that show a correlation between parkinsons symptoms and low levels of Uric Acid, and state that treatment with UA (Inosine) holds much promise for the treatment of Parkinsons (3, 4, 5)

However, if Uric Acid is too high in the body there are risks, the formation of Uric Acid Kidney stones, which although can be passed without medical treatment are still painful, and also an increased risk of Gout, neither of those sound very appealing, but at this point I would glady trade my symptoms for kidney stones and gout, and Im hopeful that if treatment was successful in scavenging the peroxinitrite, that other interventions could be put in place to control the production of future peroxynitite...for example

LIMIT THE NITRIC ACID PRODUCTION

This is the next port of call, studoes into the brains of patients with MS, Parkinsons, demntia and alzeimers all present with higher than normal levels of Nitric Oxide..so what can I put in place to lower these levels?

1) avoiding L-arginine and L-arginine rich foods.

2) avoiding exercise that causes the heart rate to go up - this causes the production of NO.

3) avoid vitamin D, especially D3 (6)

4) AVOID VITAMIN E (7)

5) Avoid foods high in histamine (8) It seems that we have another cycle here, histamine causes an increase in NO, and NO causes an increase in mast call activation (see previous blog post for more on this)

6) Have iron/Folic acid levels checked, Iron can bind to NO and that renders the Iron inactive - it seems ferritin is the best choice of supplement in this case, but again so much caution has to be used in supplementing when suffering with withdrawal syndrome.
''it is likely that adequate ferritin levels act to reduce some of the negative effects of excess NO through its antioxidant function. NO in turn, helps to protect against the release of oxidative free iron from iron-containing compounds (Puntarulo 97, Juckett 96)'' (8)

7) L-LYSINE - l-lysine is an inhibitor of L-arginine uptake, therefore it stands to reason that supplementing with Lysine could quell the overproduction of NO by making less available Arginine ...in one study on rats, L-arginine was tested to see if this theory would work, the conclusion was  as follows...

''l-lysine, an inhibitor of cellular l-arginine uptake, reduces NO production and exerts beneficial haemodynamic effects in endotoxaemic rats. l-lysine also reduces hyperlactataemia and tends to blunt the development of organ injury in these animals. Contrastingly, l-lysine has no effects in the absence of endotoxin and thus appears to act as a selective modulator of iNOS activity.'' (9)

another study, conducted on NO levels in pigs lungs concluded with this statement
''We found that increasing the vascular Larginine concentration increased NO production in both groups, furthermore, these experiments provided evidence for the forst time that inhibiting L-arginine uptake using L-lysine decreased NO in the pig Lung'' (10)

Now, you may be thinking, but this is in the BRAIN not the body, well perhaps this is where our weakened and leaky BBB is to our advantage. :)

8) Acetyl-L-carnitine - I am very leery of this particular substance as it crosses the BBB, although as everything in our bodies crosses the BBB due to its degrading im trying to keep an open mind, I will readdress this supplement once I have done more research on it.



ok, last but certainly not least, would be to control or inhibit the production of Superoxide...this is once again, tricky business, but it can be done...

1) The way to keep superoxide lower and counter its deleterious effects is with a substance called superoxide dismutase...or SOD.

In a study called Superoxide dismutase overexpression protects dopaminergic neurons in a Drosophilia model of parkinsons disease -  tests were carried out to see if SOD would have an impact on the disease..the finding were as follows

''We show that dopaminergic neurons are specifically sensitive to hyperoxia induced oxidative stress and that mutant forms of alpha-synuclein show an enhanced toxicity under these conditions suggesting synergic interactions. In addition, the co-expression of Cu/Zn superoxid dismutase protects against the dopaminergic neuronal loss induced by mutant alpha-synuclein overexpression thus identifying oxidative stress as an important causative factor in the pathology of autosomal-dominant Parkinsonism.'' (11)

another Parkinsons study indicates that SOD decreases over time/duration of the disease

''A negative correlation between SOD activity and duration of the disease was observed, while there was no relationship between L-Dopa treatment and SOD activity'' (12)

But supplementing with SOD is not easy, the SOD protein is easily deactivated by the harsh acids and enzymes contained in the digestive tract...hoever scientists discovered that coupling the SOD molecule with a protective protein derived from wheat or other plants, it could be delivered intact
to the intestines and absorbed into the bloodstream. 

In which case the only way enhance SOD in the body would not be through food groups where the molecule is quickly destroyed and rendered useless but through the supplement SOD/gliadin.

So that concludes my thinking for today, that by conbining the use of Inosine, SOD/gliadin and L- lysine, the dangers of peroxynitrite could be ameliorated, its not certain, far from it, but its the best Ive got.....for now......












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Friday 22 November 2013

Toxic encephalopathy caused by the taking or withdrawal from psychiatric drugs could be primarily caused by Nitric Oxide. and the steps we can take to heal.

Before anyone reads this or makes a judgment I want to state that this is all the opinion of one person (me lol), I dont not state this as fact, but my personal hypothisis for what is at the root cause of the symptoms of psych med withdrawal

I first came across Nitric Oxide just a few days ago,  17 months into my extremely severe withdrawal syndrom from the SSRI medication Citalopram, as well as suffering a huge adverse reaction to trying to reinstate, I spend my time, as many others have before me, researching and trying to understand what is happening to me, and WHY,  and how we could put things in  place to at least help with healing, or stop further destruction...there had to be something ...right??

In November 2013 I stumbled accidentally across a story from a young man who had taken a Nitric Oxcide (NO) boosting supplement, claiming to increase NO by 950%...his reaction was catastrophic and degenerative and he continued to try drug after drug to make things better...

His symptoms so mirrored those of us who are suffering from what we call protracted withdrawal that I began to look for links between NO and withdrawal syndrome...

It is my belief, and has been for some time, that 'withdrawal' is a misnomer..I believe Dr Stuart Shipko is correct when he speaks of Toxic Brain Damage...many of us in withdrawal understand this fact but continue to use the term withdrawal for ease as it is what we have come to accept and understand, but the realities of this Toxic brain damage are, in my opinion, much more sinister

People tell me that time heals, and from what I have read and seen, yes, time has improved everyone I have read about or communicated with, and if you are able to function somewhat during this ''withdrawal'' period, then waiting it out is a good idea.

However, some of us, and Im yet to find anyone as severe as I, are looking at many many yaers of intense suffering, before even seeing small improvements, so I am searching out answers and will not stop..never..until Im healed

Something I think we all of us in withdrawal crave is to understand what is happening to us...to give us some sense of control, or take away some of the mystery and therefore fear of our own terrible condition, personally I think we need to turn to the SPECT scans, as its the only thing that has reliably shown up the damage done.

I know of 6 people who whilst in withdrawal have had a SPECT scan..each of these people have shown the same results...severe Hypoperfusion to areas of the brain, mainly the temporal lobes and frontal cortex..

(I would be most interested in hearing for anyone who has had a SPECT in withdrawal and what the findings were.)

I am aware that some people in the withdrawal community disregard these scans, I do not.

We know that SPECT scans show the damage, and we know that the damage causes severe blood flow restrictions to parts of the brain.

So an obvious answer for this would be Hyperbaric Oxygen therapy...and this is high on my list of treatments to use...its controversial, and some have tried it but with little success, but their protocol could have been entirely wrong..However, this post is not about HBOT, I will be writing about that soon

The reason I brought up the whole HBOT issue is that it DOES increase NO in the brain and this is very worrying as I believe NO to be what is poising us and killing our brain cells..

So....lets start by looking at what exactly NO is...Wiki describes it at this...

Nitric oxide, or nitrogen oxide,[2] also known as nitrogen monoxide, is a molecule with chemical formula NO. It is a free radical[3] and is an important intermediate in the chemical industry. Nitric oxide is a by-product of combustion of substances in the air, as in automobile engines, fossil fuel power plants, and is produced naturally during the electrical discharges of lightning in thunderstorms.

In mammals including humans, NO is an important cellular signaling molecule involved in many physiological and pathological processes.[4] It is a powerful vasodilator with a short half-life of a few seconds in the blood. Long-known pharmaceuticals such as nitroglycerine and amyl nitrite were discovered, more than a century after their first use in medicine, to be active through the mechanism of being precursors to nitric oxide

The Nitric Oxide Society are full of praise for this wonder molecule, and indeed it plays a vital role in our biochemistry, but like so many things, an excess can be so SO damaging

This was taken from a forum where a poster had recieved an article from dr. michale colgan ( famous nutritionist ) also author of famous book optmium sports nutrition

Nitric oxide is manufactured by an enzyme called nitric oxide synthase, which turns the amino acid L-arginine into citrulline and nitric oxide, both of which serve multiple bodily functions. 
Throughout the brain, nitric oxide is an essential chemical messenger, which improves communication between neurons, release of neurotransmitters, and transmission and storage of information.1,2 

Nitric oxide is also a free radical, what is called a reactive nitrogen species (RNS), but is relatively benign.1,3 Like many other biochemicals, however, it can multiply out of control. Then it cooks your brain. It happens like this. Various stressors, such as banging your head against a brick wall, cause certain defensive genes to turn on and cause the brain to manufacture pro-inflammatory gremlins called cytokines. These nasty little beggars stimulate the glial cells to produce large amounts of the inducible form of the enzyme nitric oxide synthase. The enzyme then gobbles up all the spare L-arginine and produces a ton of nitric oxide, which overwhelms other control chemicals and causes raging inflammation. Result: damaged brain cells all around. 

The Glutamate – Nitric Oxide Link
Fear, anger and air pollution, also damage the mitochondria and reduce the supply of ATP.2,4,5 The protective electric fences around outer cell membranes lose power, and unwanted substances leak into the cell. Particularly opportunistic is the neurotransmitter glutamate, responsible for fast, excitatory neural transmission, just the sort of brain activity that increases in fear and anger situations. Glutamate attacks what is called the n-methyl-d-aspartate (NMDA) receptors on neurons, making a sort of hole through which calcium and other nasties can leak into the cell.2

Calcium is very nasty when it gets into the wrong place, as anyone who has had a heel spur or a calcified artery can attest. In brain cells it converts an enzyme called xanthine dehydrogenase to xanthine oxidase, a process which produces a mass of superoxide free radicals.6,7 Then all hell breaks loose. The excess nitric oxide already being produced by the brain stressor, combines with the superoxide to make the extremely damaging free radical peroxynitrite (0N00-).6,7 Peroxynitrite damages mitochondria, DNA, other proteins in brain cells and any other tissues that get in its way.6,8 

Some of these clues come from recent research on the brain damage caused by drugs such as methamphetamine, damage that is very like early Alzheimer’s. In a representative study, Imam and colleagues at the US National Center for Toxicological Research, in Jefferson, Arkansas, showed that peroxynitrite is the major culprit.8 With every step of evidence, science is tying the brain damage caused by a wide variety of stressors to the major forms of dementia.
Links To Alzheimer’s

Cholinergic neurons in the hippocampus of our basal forebrain, express the neurotransmitter acetylcholine. These cells are more primitive in evolution than cholinergic cells in the cerebral cortex. They evolved in the brains of short-lived, ferocious animals, and are designed for shorter, more violent life than those in the cerebral cortex. They have higher levels of nitric oxide, to speed neural transmission for violent action, and lower levels of endogenous antioxidants, because they did not have to last very long. So they are more vulnerable to damage, and are the first to go in neurodegeneration. 

It is exactly these hippocampus structures that show the most damage in Alzheimer’s disease, with large numbers of dead and dying cells, amyloid plaque blocking neural transmission, damage to mitochondrial DNA, and useless tangles of neurofibrils.9 In cell culture studies, the amyloid plaque itself causes further release of nitric oxide, thereby creating a vicious and progressive cycle of damage.10 Alzheimer’s patients also have increased brain levels of inflammatory cytokines, which as we saw above, increase production of nitric oxide even further.11

Similar mechanisms have now been found in multiple sclerosis. Inflammatory cytokines stimulate glial cells to produce nitric oxide by way of the enzyme nitric oxide synthase, which then increases peroxynitrite to cause extensive mitochondrial damage.12 Bagastra and colleagues at Thomas Jefferson University, recently found excess levels of nitric oxide synthase in every one of the brains of deceased multiple sclerosis patients, but in none of the control brains of people who had died without brain disease.13 Induced Parkinson’s disease in animals in which the substantia nigra cells are deliberately damaged, shows the same pattern of enzyme activation.14 So does Huntington’s disease.15 

Stroke patients also show large increases in inflammatory cytokines and nitric oxide synthase, even up to three months after the stroke.16 Cerebral ischemia (restriction of blood supply) is also related to excessive glutamate stimulation of the NMDA receptor, with elevation of intracellular calcium and induction of nitric oxide synthase, which then raises nitric oxide levels.7 

There are now hundreds of similar studies in the medical literature. In a major review of the research in October 2000, renowned expert on brain chemistry, Vittorio Calabrese, of the University of Catana in Italy, shows how this process occurs repeatedly with the stresses of usual urban life. He also reviews numerous other studies, showing that damage caused by excess nitric oxide is crucially involved in Alzheimer’s, Parkinson’s, Lou Gehrig’s disease (amyotrophic lateral sclerosis, ALS) Huntington’s disease and multiple sclerosis.1 Other researchers have shown that the same process of damage is a major determinant of the dementia caused by stroke, and by other forms of oxygen deprivation of the brain, and of various forms of brain seizure.15,16 Finally, the same process is implicated in common forms of epilepsy.17 

Overall, the evidence shows that the brain degeneration caused in almost every one of us by excess nitric oxide, is also a major part of all common dementias, stroke and even epilepsy. I have covered only a fraction of these new discoveries in this short chapter, but I hope it is a representative and convincing fraction. If you fail to protect the brain from excess nitric oxide, then all other efforts to maintain your intelligence will come to naught.

This article can be viewed in full at the bottom of this blog (1)

In 2007 the Sahlgrenska Academy completed a dissertation that examined the effects reduced amounts of nitric oxide have on the symptoms of schizophrenia...the results were very interesting...
Research performed for the dissertation found that rats with characteristics of schizophrenia regain normal brain function if they receive drugs that reduce the production of nitric oxide in the brain

what was even more interesting for me was the comments under the article (2) 

one reader remarked ''I could have told you this 10 years ago as I have repeatedly told my psychiatrists that my illness was triggered by taking the sports supplement l-arginine which is known to raise nitric oxide levels. An internet or vitamin book search will allways bring up the information that l-arginine should be avoided by people suffering from schizophrenia but doctors and researchers have not cottoned on to this yet.''

and another said ''I also took l - arginine and became psychotic and schizophrenic, the dosage was not high when I took it, but when an episode of major stress happened in my life I took this supplement to ameliorate it but I became psychotic. Unfortunately I was also predisposed to this ilness becouse I have positive family history''

So, why do I think that NO is responsible for our issues? a few reaons, NO we know increases during any brain trauma, well CT from psych drugs or indeed the impact of removing them at all is 100% a trauma to the brain, thus it increases NO...I also believe that any ''setback'' one encounters triggers a release of NO....this build over time to a critical mass causing first the delayed onset of SSRI withdrawal, and then subsequent ''waves'' of severe symptoms.

This study shows the impact of AD removal on NO levels  http://www.ncbi.nlm.nih.gov/pubmed/16865538


There are many other known factors that can trigger a wave but I feel they can all come back to NO

1) Stress - we all know the term Oxidative Stress, it can be argued that adrenaline if not used for fight or flight can be turned into NO.

2) Diet, now this is where it gets really interesting....It has been well written about on the beyond meds site that Histamine intolerance seems to be relevant to psyc drug withdrawal, and we speculate that this is because alot of psyc drugs were made from antihistamine and that we are in some kind of rebound state from that....but what if Nitric Oxide is behind it all?

Martin L. Pall, Professor of Biochemistry and Basic Medical Sciences 
Washington State University ...wrote an article called

 A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia and Posttraumatic Stress Disorder

he points the finger at NO being responsible for all of these issues of the CNS (3)

and he says this

  • mast cells which release histamine are activated by both nitric oxide and vanilloid stimulation (Chapter 7) and may therefore be part of the cycle mechanism
MAST CELLS ARE ARE ACTIVATED BY NITRIC OXIDE!!!!

it is the NO, causing the histamine intolerance

also Dr M.L Paull states -  ''Excitotoxins can stimulate NMDA activity and up-regulate NO/ONOO- cycle biochemistry and should therefore be avoided. Excitoxins include monosodium glutamate, aspartame and possibly certain other flavorings such as hydrolyzed vegetable protein''

and thats another thing we know to avoid in withdrawal, but not because it upregulates NO...who knew?!?!?!

So those are some of the reasons I believe that Nitric Oxide is the ROOT CAUSE of the symptoms and presentation of withdrawal syndrome

So what can we do about it?????

Thats what I will be writing about over the next few days, there are ideas, some we are doing already, but not with NO in mind, and some we can think about



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