Inosine As A Powerful Inhibitor Of Serotonin And Cortisol Synthesis

haidut

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As many of you know, I have been reading older Russian studies on many of the substances Peat talks about. He mentioned inosine in one of is articles, but only in relation to improving immunity and preventing dementia.
The problem of Alzheimer's disease as a clue to immortality Part 1
"...Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another natural substance (found in meat, for example) which is a component of "inosiplex," an antiviral drug (Brown and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., "Adenosines scavenged hydroxyl radicals and prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4), 473-479, 1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors in rat brain synaptosomes: Transductional mechanisms, efects on glutamate release, and preservation after metabolic inhibition," Drug Develop. Res. 35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450 enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence of penicillin."

Inosine is a component of a number of Russian drugs that were developed in the 1960s and 1970s and the most commonly used one is cytoflavin. Inosine is known as a potent cardioprotector and has been shown (in Russian studies) to prevent and reverse heart failure, and its main use in Europe today remains as a immunostimulant and cardioprotector. It inhibits lipolysis, increases glucose oxidation, increases mitochondrial biogenesis, and is considered an actoprotector - a substance that increase physical performance. Unfortunately, inosine got bad press in the Western world as a few studies with short-term (or even single) dosing showed no performance improvements. The full effects of inosine as an anabolic agent are visible after 30-60 days and most of those effects come from its ability to restore (or even increase) ATP levels. Inosine is breakdown product of ATP but there is the so-called purine salvage pathway, which can convert inosine back to adenosine->AMP->ADP->ATP.
I will make a more detailed review of inosine in another thread, but two studies that caught my eye were the ability of hypoxanthine (an immediate byproduct of inosine when taken orally) to potently lower serotonin synthesis/release. The study was in humans and used 1g hypoxanthine x 3 daily. The same dose of inosine should have comparable effects, but older studies with power lifters (especially in Bulgaria, Hungary and other Eastern Block countries) have used a dose of up to 50mg/kg (human dose) daily in divided doses. The second study shows that one of the likely mechanism of actions of hypoxanthine (and thus inosine) is a fairly selective MAO-B inhibition, which results in elevated dopamine levels. The HED from the second study (animal) matches quite well the 1g x 3 daily human dose from the first study, but it also shows that hypoxanthine doses as low as HED 2mg/kg (25mg/kg for mice) work too. MAO-B inhibitors have been shown to extend maximum lifespan in all animal models tested so far and the MAO-B inhibitor selegiline (Selegiline - Wikipedia) is a (ab)used by athletes and celebrities as an anti-aging and performance enhancing drug. As such, selegiline is banned by IOC/WADA as a doping agent. Well, it looks like humble inosine may be able to offer a great deal of the same benefits for a fraction of the cost. I don't know if inosine has a similar mechanism of action to pCPA (Fenclonine) but it may be able to achieve the same effects.
The only drawback to inosine is its ability to raise uric acid, which can exacerbate gout and can increase risk of kidney stones. Interestingly, older Russian studies show that higher doses of inosine are less likely to raise uric acid because inosine is an inhibitor of xanthine oxidase, and thus impedes uric acid formation. As far as I can remember the IC50 of inosine for xanthine oxidase was 80 uM/L, and that should be achievable with doses of 500mg or higher.
Finally, given the well-known relationship between serotonin and cortisol, a chemical that lowers serotonin synthesis is expected to lower cortisol levels as well. The human study did find lower cortisol too, as expected. In fact, the drop in cortisol by the 10th day was by a whopping 62% - a decrease almost identically matching the 60%+ decrease in serotonin.

Reduced urinary serotonin excretion after intake of high doses of hypoxanthine. - PubMed - NCBI
"...Two healthy volunteers were treated with hypoxanthine 3 x 1 g and allopurinol 3 x 100 mg daily for 1 week. During this treatment serum oxypurine concentration and urinary oxypurine excretion increased as expected. No side effects were observed except for some mild daytime drowsiness and lethargy. Measurements of urinary serotonin (5-HT) excretion showed decreases to as much as 60% below initial values. Decreased urinary 5-HT excretion was also found in a patient with incomplete Lesch-Nyhan syndrome during treatment with high doses of hypoxanthine. His neurological symptoms improved slightly. The results suggest that high doses of hypoxanthine exert a nonspecific sedative effect on both patients with Lesch-Nyhan syndrome and healthy controls. The cause is probably a reduced synthesis or release of 5-HT."

"...This suggests that the source of the problem is far remote from the locus of 5-HT synthesis. However, the decrease of the 24h urinary 5-HT excretion in our patient with incomplete Lesch-Nyhan syndrome as well in the two healthy controls after treatment with high doses of hypoxanthine suggests that purine metabolites may reduce the synthesis or the release of 5-HT in different tissues."

"...Parallel increased plasma levels of 5-HT and cortisol have been found in patients at the beginning of surgery and a postoperative return to presurgery levels [5]. Our results in the patient with incomplete Lesch-Nyhan syndrome show that high doses of hypoxanthine have a sedative affect accompanied by decreased cortisol and 5-HT values in both blood and urine. It is well known that different kinds of stress lead to increases in the secretion of adrenocorticotropic hormone, cortisol, noradrenaline, histamine, and 5-HT. Sedative drugs, however, diminish the secretion of these stress hormones. Treatment with high doses of hypoxanthine has a nonspecific sedative effect not only in patients with incomplete LeschNyhan syndrome but also in healthy controls probably due to a reduction in 5-HT secretion. It was suggested (W. Nyhan personal communication) that in our particular case of incomplete Lesch-Nyhan syndrome (6.9% HGPRT activity) a slight increase of his HGPRT activity would reduce his neurological symptoms. Since patients with an activity as low as 7.2% did not show neurological symptoms [12], we sought to increase the HPRT activity of our patient through elevating his hypoxanthine concentration in the tissues, especially in the brain. Our additional results suggest that the positive effect of the hypoxanthine treatment was a general pharmacological rather than a specific effect. The results support the hypothesis [11] that purine metabolites are able to modulate the release or the synthesis of neurotransmitters.

[Inhibitory effect of hypoxanthine on monoamine oxidase activity]. - PubMed - NCBI
"...Hypoxanthine was demonstrated to have a dose-dependent inhibitory effect on type B monoamine oxidase (MAO-B) activity in liver and brain tissues, and slight inhibitory effect on type A MAO(MAO-A) activity when given orally to mice at doses of 25-500 mg/kg. When mice were given orally hypoxanthine 500 mg/kg, MAO-A and -B activities were all inhibited significantly 16 hours after administration, but the inhibitory action on MAO-A was weaker. Subcutaneous injection of the agent also produced obvious inhibition of MAO activity in the liver but no significant influence on MAO activity in brain tissue was observed. In vitro experiment showed that the action of hypoxanthine on MAO-B was competitive inhibition and that on MAO-A was competitive mixed with noncompetitive inhibition."
 
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Tarmander

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Do you think Inosine is the best ATP-like/mimic supplement you can take? Nice that you are diving into some of the older Russian stuff, seems like Peat draws a lot from those sources.
 

aguilaroja

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...Peat talks about...inosine in one of is articles, but only in relation to improving immunity and preventing dementia.

The only drawback to inosine is its ability to raise uric acid, which can exacerbate gout and can increase risk of kidney stones. Interestingly, older Russian studies show that higher doses of inosine are less likely to raise uric acid because inosine is an inhibitor of xanthine oxidase, and thus impedes uric acid formation. As far as I can remember the IC50 of inosine for xanthine oxidase was 80 uM/L, and that should be achievable with doses of 500mg or higher.
...

One recent study used inosine to raise uric acid levels, in hopes of eventually slower decline in Parkinson’s disease.
One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan. - PubMed - NCBI
It showed reasonable safety over one year. Subjects in the study started on 1000 mg/day of inosine, and the dose was adjusted between 500 and 2000 mg per day based on serum testing.

This recent study raised the possibility of intestinal tract supplementary elimination of uric acid. So good bowel transit may be especially important for inosine regimens.
Intestinal tract is an important organ for lowering serum uric acid in rats
 

haidut

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Do you think Inosine is the best ATP-like/mimic supplement you can take? Nice that you are diving into some of the older Russian stuff, seems like Peat draws a lot from those sources.

I think it is pretty good considering the low price. I think direct ATP supplemetation may be even more effective, but it is more expensive. There are recent human studies with oral ATP showing strong muscle protective anabolic effects. I will post them when we release the ATP supplement.
 

haidut

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One recent study used inosine to raise uric acid levels, in hopes of eventually slower decline in Parkinson’s disease.
One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan. - PubMed - NCBI
It showed reasonable safety over one year. Subjects in the study started on 1000 mg/day of inosine, and the dose was adjusted between 500 and 2000 mg per day based on serum testing.

This recent study raised the possibility of intestinal tract supplementary elimination of uric acid. So good bowel transit may be especially important for inosine regimens.
Intestinal tract is an important organ for lowering serum uric acid in rats

Inosine also lowers NO synthesis systemically and I think this is one of the primary beneficial effects. That and of course its effects on metabolism.
Inosine Powerfully Stimulates Mitochondriogenesis, Oxidative Metabolism & Cell Differentiation
 

Regina

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I think it is pretty good considering the low price. I think direct ATP supplemetation may be even more effective, but it is more expensive. There are recent human studies with oral ATP showing strong muscle protective anabolic effects. I will post them when we release the ATP supplement.
:cool
 

PhilParma

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I want to experiment with adrenaline crushing moderate-to-high doses of inosine. Cardenosine has a rather low amount per dose. Pure Encapsulations doesn't carry inosine. I don't know what other sources to trust.

What is a good source of supplemental inosine?
 

Regina

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I want to experiment with adrenaline crushing moderate-to-high doses of inosine. Cardenosine has a rather low amount per dose. Pure Encapsulations doesn't carry inosine. I don't know what other sources to trust.

What is a good source of supplemental inosine?
I use AnabolNaturals brand. I get the powder on amazon prime.
 

meatbag

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I want to experiment with adrenaline crushing moderate-to-high doses of inosine. Cardenosine has a rather low amount per dose. Pure Encapsulations doesn't carry inosine. I don't know what other sources to trust.

What is a good source of supplemental inosine?
haidut just released a supplement with inosine: Cardenosine
 

Regina

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What has been your experience with it?
I used it temporarily during a period of experiencing sudden breathlessness, racy heart and exercise intolerance in aikido. All the symptoms of elevated norepinephrine. I used inosine about 1 gram per day for about 2 wks. I know the feeling of adrenalin/NE. That course of inosine completely stopped the problem.
I no longer take it unless I do a hit of cardenosine.
To be honest, I think my adrenalin/NE are now flat-lined. But I am able to take T3 now with zero feelings of rT3.
I'm convalescing in Florida now and not training and holding onto my cardenosine for when I go back to training.
I still have not been able to reverse a lung issue and hoping living/sleeping with the windows open will resolve it. I'm at a loss what to do about my crappy lungs.
I've tried everything talked about on the forum.
 

ddjd

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I want to experiment with adrenaline crushing moderate-to-high doses of inosine. Cardenosine has a rather low amount per dose. Pure Encapsulations doesn't carry inosine. I don't know what other sources to trust.

What is a good source of supplemental inosine?
I've tried a few brands. Do not buy from Swanson. It's complete crap.

The best one is by cardiovascular research. It's a liposomal form. Works very very effectively. And definitely reduces Serotonin too.

They stopped manufacturing it but loads of places still have it in stock so I would get as much whilst its still available
 

PhilParma

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Anabol Naturals has no silicon, but @Joeyd's CR recommendation is so strong...my high-serotonin state is making me so indecisive.
 
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