Schizophrenia Treatment Could Be As Simple As Reducing Ammonia

haidut

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I posted a number of studies on Ceylon cinnamon and its metabolite sodium benzoate, showing their benefit in Parkinson disease, depression and anxiety. While all of those studies were on animal models, the toxicity of ammonia in the brain is undisputed and its role in all of these disease has been acknowledged even by mainstream doctors. The animal studies focused on the role of nitric oxide (NO) in the pathology of those conditions, but a more important factor could be ammonia buildup in the brain (which sodium benzoate chelates). Btw, sodium benzoate is even approved by the FDA as a drug (Ucephan) to treat hepatic encephalopathy due to ammonia accumulation. Peat also spoke about the role of ammonia in mental diseases like schizophrenia and the benefits of reducing its accumulation.
Thyroid, insomnia, and the insanities: Commonalities in disease
"...Lithium forms a complex with the ammonia molecule, and since the ammonia molecule mimics the effects of serotonin, especially in fatigue, this could be involved in lithium’s antiserotonergic effects. Ammonia, like serotonin, impairs mitochondrial energy production (at a minimum, it uses energy in being converted to urea), so anti-ammonia, anti-serotonin agents make more energy available for adaptation. Lithium has been demonstrated to restore the energy metabolism of mitochondria (Gulidova, 1977). Therapies that have been successful in treating “schizophrenia” include penicillin, sleep therapy, hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin, histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and increased carbon dioxide acidifies cells, preventing serotonin secretion."

This new study is a human one, and it used pre-formed sodium benzoate as an add-on to standard drugs (clozapine) for treatment-resistant schizophrenia. This form of schizophrenia is especially pernicious as most patients do not respond to any drug treatment and there is very little modern medicine can do for them except keep them chronically sedated and possibly locked up - i.e. pretty much zombies for life.
The study found dose-dependent improvements beyond what clozapine on its own was able to achieve. The doses used were 1g and 2g daily and duration of treatment was 6 weeks. Perhaps most importantly, there were no side effects, which is huge news as established treatments for schizophrenia (including clozapine) have terrible side effects which makes patients often refuse to take the drugs voluntarily.
The officially proposed mechanism of action is the ability of sodium benzoate to inhibit D-serine breakdown, however I think the much more likely explanation is the reduction of ammonia in the brains of those patients.
@aguilaroja @Travis

http://www.biologicalpsychiatryjournal.com/article/S0006-3223(17)32297-7/fulltext
Food preservative enhances schizophrenia treatment
"...The common food preservative sodium benzoate improves symptoms in clozapine-resistant schizophrenia patients, according to a new study published in Biological Psychiatry. The randomized, double-blind, placebo-controlled trial led by Hsien-Yuan Lane, M.D., Ph.D., of China Medical University, Taiwan, showed that adding on sodium benzoate to the antipsychotic clozapine improved symptoms in patients who did not see results with any other medications, providing a new option for the hardest-to-treat patients.
Clozapine is considered the last-line antipsychotic agent for patients with refractory schizophrenia,” said Dr. Lane, referring to patients whose symptoms do not respond to available antipsychotics. But an estimated 40–70 percent of patients with refractory schizophrenia fail to improve even with clozapine, referred to as “clozapine-resistant”, exhausting all potential options for treatment. The new study is the first to demonstrate that sodium benzoate—which has been shown to enhance other antipsychotic drugs—works in clozapine-resistant patients.
“If the finding can be confirmed, this approach may bring hope for treating patients with the most refractory schizophrenia,” said Dr. Lane.
The 60 patients with schizophrenia included in the study were all taking clozapine, and received a placebo or sodium benzoate as an add-on treatment for six weeks. First author Chieh-Hsin Lin, M.D., Ph.D., of Chang Gung University College of Medicine, Taiwan, and colleagues tested two different doses of sodium benzoate (1 or 2 grams per day) to find which offered the biggest impact on symptoms with minimal side effects.
Compared with the placebo, sodium benzoate improved negative symptoms, such as lack of emotion and motivation, which have a greater influence on a patient’s functional outcome than the more prominent psychotic symptoms. The higher dose of sodium benzoate also improved ratings of overall symptoms and quality of life. Although sodium benzoate has improved cognitive function when combined with other antipsychotics in previous studies, the add-on treatment had no influence on cognitive function in this study—in the paper, Dr. Lin and colleagues suggest that a higher dose or longer duration of treatment may be needed for these effects. Importantly, the patients taking sodium benzoate had no side effects, confirming the treatment is safe to use at the doses tested.
Sodium benzoate works by preventing the breakdown of D-serine, a brain chemical that plays an important role in signaling that is disrupted in the brains of people with schizophrenia. “Receptors for D-serine are long-standing targets for medication development in schizophrenia and sodium benzoate is probably the first meaningful tool that we have had to influence this target,” said John Krystal, M.D., Editor of Biological Psychiatry. Although more studies are needed to learn how sodium benzoate enhances clozapine treatment in these patients, Dr. Krystal says that “this study highlights the importance for schizophrenia treatment of understanding the molecular switches that can be thrown to normalize brain circuit function.”
 

aguilaroja

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I posted a number of studies on Ceylon cinnamon and its metabolite sodium benzoate, showing their benefit in Parkinson disease, depression and anxiety. While all of those studies were on animal models, the toxicity of ammonia in the brain is undisputed and its role in all of these disease has been acknowledged even by mainstream doctors....

This new study is a human one, and it used pre-formed sodium benzoate as an add-on to standard drugs (clozapine) for treatment-resistant schizophrenia....
The officially proposed mechanism of action is the ability of sodium benzoate to inhibit D-serine breakdown, however I think the much more likely explanation is the reduction of ammonia in the brains of those patients.

[The new study is the first to demonstrate that sodium benzoate—which has been shown to enhance other antipsychotic drugs—works in clozapine-resistant patients.
“If the finding can be confirmed, this approach may bring hope for treating patients with the most refractory schizophrenia,” ...

Thank you. The finding about excess ammonia is most important. In limited anecdotal experience, people I knew using supplementary serine for cognitive/mood issues had equivocal results.

This paper got me wondering if the “sodium” part of sodium benzoate may be as primary in reducing ammonia:
Saline is as effective as nitrogen scavengers for treatment of hyperammonemia
“In CPSS-dogs, treatment with SB [sodium benzoate] resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste.”

Of course, in the world of medical commerce, salt/saline, a relatively safe, cheap and simple substance, is regarded as “placebo”.

Epilepsy and Progesterone
“Ammonia is produced by stimulated nerves, and normally its elimination helps to eliminate and control the excitotoxic amino acids, glutamate and aspartate. The production of urea consumes aspartic acid, converting it to fumaric acid, but this requires carbon dioxide, produced by normal mitochondrial function.”
 

Travis

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Well, I generally ascribe to the Histamine Theory of Schizophrenia so you're post got me wondering about how it could be superimposed onto that. The first impression I got from clozapine was its similarity to cyproheptadine. Now that it's a confirmed antischizophrenic I'll have to see if it has affinity for the H₁ or H₂ receptors:

Okay, I found another person to seems to ascribe to the Histamine Theory:

Mancama. "Investigation of promoter variants of the histamine 1 and 2 receptors in schizophrenia and clozapine response." Neurosc. letters (2002)

'Such alterations have also been proposed to arise through histamine receptor desensitisation in response to increased histamine turnover, following evidence for significant elevation of the primary histamine metabolite telemethylhistamine amongst patients [15].' ―Mancama

'Histamine H1 receptors are known to be targeted with high affinity by several atypical antipsychotics, particularly clozapine [7], and the drugs action at this receptor may contribute towards its unique therapeutic efficacy.' ―Mancama

'Unlike the H1 receptor, clozapine and similar antipsychotics are not known to specifically target the H2 receptor.' ―Mancama

They cite the study which had shown a 2.6× increase in brain histamine among schizophrenics [15], and Dr. Mancama confirms my suspicion by stating that clozapine activates the H₁ receptor [7] in addition to providing insight that the H₁ receptor—and not the H₂ receptor—is involved.

But the citation for the H₁ binding data is an impossible‐to‐obtain book, so it's hard to compare it directly to cyproheptadine.

[7] B.A. Ellenbroek. "Atypical Antipsychotics. Milestones in Drug Therapy." Verlag AG (2000)
[15] Prell, G.D. "Histamine metabolites in cerebrospinal fluid of patients with chronic schizophrenia: their relationships to levels of other aminergic transmitters and ratings of symptoms." Schizophrenia Research (1995)
 
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I was interested in sodium benzoate a while back, I actually used to eat ceylon cinnamon quite a lot, and tried to buy some raw sodium benzoate powder, but accidentally got potassium sorbate instead.

Ceylon cinnamon contains coumarin, though lower than cassia cinnamon, still a problem (vitamin K antagonist), and ceylon is expensive, so I discontinued that.

And sodium benzoate itself actually inhibits HMG-CoA, the same target of statins. Not good, I want cholesterol synthesis pathways working 100%.

https://i0.wp.com/www.ncbi.nlm.nih.gov/pmc/articles/PMC3206174/bin/nihms307987f1.jpg

Edit:

For lowering ammonia, making sure protein intake is at sufficient levels, and absolutely no more that that.

Even more relevant would be to find a way to lower the oxidation of amino acids for energy. That should never be used, ever, glucose/fatty acids/ketones, but never amino acids. They should only ever be used for structure or mechanical work, not the fuel that powers those things.

My first thought in regards to preventing amino acid oxidation would be to make sure you're well fed, and that muscles are NEVER catabolized, meaning androgens(?) or anti-glutocorticoids measures (no direct antagonists though).

Keto-acids also seem helpful (I don't understand the pathways well enough yet though..), but people should be aware that the biggest keto-acid found in food, alpha-ketoglutaric acid, turns into glutamic acid when donated the amine group (when the ammonia is sequestered).
 
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Lactulose is used effectively to reduce ammonia.

Lactulose's MOA seems to be the acidification of the colon via fermentation by flora there, I'm guessing by being metabolized into lactate.

Hahah, I just looked and I was right! It's metabolized into lactate and acetate in the intestines.

This is my guess: normally, the colon is slightly basic, which allows the absorption of many basic components in the diet. When lactulose is consumed, and things like acetic acid and lactic acid are formed, the colon is made acidic, and particles are ionized and unable to absorbed.

The official explanation on wikipedia is that the ammonia is turned into ammonium (NH4+), which isn't absorbed.

I think this explanation also explains the electrolyte imbalances that are sometimes experienced from lactulose. The ionized and charged electrolytes are unable to be absorbed.

Lactulose seems like a horrible way to reduce ammonia.

I wonder what ammonia is even doing in the small intestines. Is all endogenously produced ammonia pumped into the blood and then deposited into the insides of the small intestines, where it's excreted? Why else would all this ammonia be there, is ammonia produced directly in the small intestines via fermentation of protein? If so, a simple way to reduce ammonia in the blood and tissues would be to kill the flora.
 

Lucenzo01

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Lactulose's MOA seems to be the acidification of the colon via fermentation by flora there, I'm guessing by being metabolized into lactate.

Hahah, I just looked and I was right! It's metabolized into lactate and acetate in the intestines.

This is my guess: normally, the colon is slightly basic, which allows the absorption of many basic components in the diet. When lactulose is consumed, and things like acetic acid and lactic acid are formed, the colon is made acidic, and particles are ionized and unable to absorbed.

The official explanation on wikipedia is that the ammonia is turned into ammonium (NH4+), which isn't absorbed.

I think this explanation also explains the electrolyte imbalances that are sometimes experienced from lactulose. The ionized and charged electrolytes are unable to be absorbed.

Lactulose seems like a horrible way to reduce ammonia.

I wonder what ammonia is even doing in the small intestines. Is all endogenously produced ammonia pumped into the blood and then deposited into the insides of the small intestines, where it's excreted? Why else would all this ammonia be there, is ammonia produced directly in the small intestines via fermentation of protein? If so, a simple way to reduce ammonia in the blood and tissues would be to kill the flora.

I read a while a go that lactulose feed gram-positive bacteria in the colon. They consume ammonia while gram-negative bacteria produce it. So, increasing the amount of gram-positive bacteria would help to reduce the ammonia load. I have an uncle that swears by it. I experimented a while ago with it with mixed results.
 

M-dog

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TreasureVibe

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Hveragerthi says that increasing GABA levels helped his schizophrenia patients, and also raising oxytocin because it lowers dopamine which is related to schizophrenia.
 

Pointless

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@haidut do you think the schizophrenic-like symptoms from large, continuous doses of caffeine are also caused by ammonia?
 

haidut

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@haidut do you think the schizophrenic-like symptoms from large, continuous doses of caffeine are also caused by ammonia?

Yes, and cortisol is also likely involved if enough caffeine is taken to trigger heavy lipolysis and a stress reaction.
 

astral kid 2

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I was interested in sodium benzoate a while back, I actually used to eat ceylon cinnamon quite a lot, and tried to buy some raw sodium benzoate powder, but accidentally got potassium sorbate instead.

Ceylon cinnamon contains coumarin, though lower than cassia cinnamon, still a problem (vitamin K antagonist), and ceylon is expensive, so I discontinued that.

And sodium benzoate itself actually inhibits HMG-CoA, the same target of statins. Not good, I want cholesterol synthesis pathways working 100%.

https://i0.wp.com/www.ncbi.nlm.nih.gov/pmc/articles/PMC3206174/bin/nihms307987f1.jpg

Edit:

For lowering ammonia, making sure protein intake is at sufficient levels, and absolutely no more that that.

Even more relevant would be to find a way to lower the oxidation of amino acids for energy. That should never be used, ever, glucose/fatty acids/ketones, but never amino acids. They should only ever be used for structure or mechanical work, not the fuel that powers those things.

My first thought in regards to preventing amino acid oxidation would be to make sure you're well fed, and that muscles are NEVER catabolized, meaning androgens(?) or anti-glutocorticoids measures (no direct antagonists though).

Keto-acids also seem helpful (I don't understand the pathways well enough yet though..), but people should be aware that the biggest keto-acid found in food, alpha-ketoglutaric acid, turns into glutamic acid when donated the amine group (when the ammonia is sequestered).
How come we couldn't use direct antagonists? Something like 6-keto-progesterone?
 
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How come we couldn't use direct antagonists? Something like 6-keto-progesterone?

Can't remember my exact train of thought then, but probably because using a glucocorticoid antagonist to prevent muscle catabolism is a blunt tool. Non-specific binding of an antagonist had potential to mess up rhythms. It'd prob work, but also probably not worth it when an androgen could be used for muscle growth.
 
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