Inosine questions (adrenaline and GABAA)

[Judd Crane]

At what dosage do the anti-adrenaline effects of inosine become apparent?

As a GABAA ligand, how can it be expected to interact with gabaergic mediciations (eg. benzodiazepines)? I've found contradictory studies on this matter:

Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior - PubMed

Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not...

pubmed.ncbi.nlm.nih.gov

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors.

The actions of nicotinamide and inosine were investigated on rat cerebellar Purkinje cells using ionophoretic and extracellular recording techniques. Ionophoretic application of nicotinamide or inosine showed that they were potent inhibitors of Purkinje ...

www.ncbi.nlm.nih.gov

 

[Hans]

At what dosage do the anti-adrenaline effects of inosine become apparent?

As a GABAA ligand, how can it be expected to interact with gabaergic mediciations (eg. benzodiazepines)? I've found contradictory studies on this matter:

Interaction between purine and benzodiazepine: Inosine reverses diazepam-induced stimulation of mouse exploratory behavior - PubMed

Inosine, 2-deoxyinosine, and 2-deoxyguanosine completely reversed the increase in exploratory activity elicited in mice by diazepam. The inhibition of exploratory behavior by purines occurred at doses that when given alone have no effect on exploratory behavior. 7-Methylinosine, which does not...

pubmed.ncbi.nlm.nih.gov

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors.

The actions of nicotinamide and inosine were investigated on rat cerebellar Purkinje cells using ionophoretic and extracellular recording techniques. Ionophoretic application of nicotinamide or inosine showed that they were potent inhibitors of Purkinje ...

www.ncbi.nlm.nih.gov

Typical doses to improve the NAD:NADH ratio, increase ATP or reverse fatty liver is about 1.5g x2 daily.
If you want to lower noradrenaline, I'd recommend looking to magnesium. Noradrenaline is high when magnesium is low and noradrenaline in excess wastes magnesium. Also, magnesium is an essential mineral whereas inosine is not.

 

[Happycat]

500mg of inosine lowers adrenaline for me, it gives me a really relaxed, euforic feeling.

 

[Judd Crane]

500mg of inosine lowers adrenaline for me, it gives me a really relaxed, euforic feeling.

Thanks. Where do you get yours?

 

[Happycat]

Thanks. Where do you get yours?

From Dolphin Fitness in Uk.

 

[dukesbobby777]

From Dolphin Fitness in Uk.

How does it compare to niacinamide? They just sound like the same thing to me with many of their mechanisms

 

[Dr. B]

Typical doses to improve the NAD:NADH ratio, increase ATP or reverse fatty liver is about 1.5g x2 daily.
If you want to lower noradrenaline, I'd recommend looking to magnesium. Noradrenaline is high when magnesium is low and noradrenaline in excess wastes magnesium. Also, magnesium is an essential mineral whereas inosine is not.

someone posted that peat said inosine causes cytokine storm? have you heard on that

 

[Hans]

someone posted that peat said inosine causes cytokine storm? have you heard on that

I have not seen it can you link where Peat said it?

 

[sweetpeat]

I have not seen it can you link where Peat said it?

I think he's referring to an email with Peat posted here: Inosine Increases NAD/NADH Ratio And Reduces Systemic Inflammation

UG:

I felt viral for over a week and began self medicating. I sent him a list of what I had on hand and some things I was taking and others were stand by. I did not want to go get tested (eventually did and was negative for COVID)

His reply:

"The inosine and isoprinosine could be creating symptoms- isoprinosine increases inflammatory cytokines. Doses of zinc shouldn't be over 10mg/day. Doxycycline is anti-inflammatory so it could help. Azithromycin also anti-inflammatory- has been proven effective in Covid."

Regarding Ivermectin he said the risks could be too much for the benefit.

He specifically stated both inosine and isoprinosine could be problematic....and only noted isoprinosine increases cytokines. I ended up dropping both and had bought a truckload for me and my family. I live outside the US and things run out quickly here.

I wrote him back and told him how surprised I was considering all the hoopla here regarding these two medicines and to that he did not respond.

I know. Bummer.

 

[Hans]

I think he's referring to an email with Peat posted here: Inosine Increases NAD/NADH Ratio And Reduces Systemic Inflammation

Thanks for sharing.
So I found this @Mr.Bollox

Science | AAAS

science.sciencemag.org

"Indeed, data supporting an immunosuppressive role for adenosine and A2AR signaling has led to the development of novel immune checkpoint inhibitor targets, such as mAb targeting CD73, CD39 and CD38, and pharmacological antagonists of A2AR, many of which are currently in clinical trials [reviewed in (28)]. However, a small body of literature has demonstrated that inosine analogs can be proinflammatory and A2AR signaling can sustain Th1/anti-tumor immunity in mice (29–31). Based on these opposing findings, we investigated whether inosine could enhance Th1 cell differentiation in vitro. Activated OVA323-339 peptide-pulsed bone marrow derived dendritic cells (BMDCs) were co-cultured with naïve OVA323-339-specific OT-II CD4+ T cells in the presence or absence of inosine. Intriguingly, the effect of inosine in terms of induction or inhibition of CD4+ Th1 T cell differentiation turned out to be context dependent. Specifically, in the presence of exogenous IFN-γ, inosine strongly boosted Th1 differentiation of naïve T cells (Fig. 3A), whereas in the absence of IFN-γ, inosine inhibited Th1 differentiation (Fig. 3B and fig. S12A)."

"In contrast, bypassing the need for A2AR signaling by using db-cAMP increased Th1 differentiation and phosphorylation of CREB in A2AR-deficient T cells, confirming that the Th1 promoting effect of inosine is dependent on A2AR signaling"

"In light of our findings, one might caution against the blockade of inosine-A2A receptor signaling for cancer immunotherapy as this may negate any positive effect provided by beneficial microbes. We suggest that A2A receptor signaling is likely an integral anti-tumor pathway for bacterial-ICB co-therapies."

As they say, it's context-specific, that when IFNg is elevated, inosine could increase TH1 differentiation. Multiple other studies show that inosine is highly anti-inflammatory, such as this one:

Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock - PubMed

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or...

pubmed.ncbi.nlm.nih.gov

"In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10.

 

[Jessie]

Perhaps the dimepranol could be altering the effects of isoprinosine in some way that's negative. Isoprinosine has roughly 3x the amount of dimepranol in it then it does inosine. So when you're taking isoprinosine you're basically only getting small amounts of inosine, but mostly you're getting dimepranol.

Regular inosine seems to be decidedly anti-inflammatory. I don't see how it could have positive effects on the NAD/NADH and GSH/GSSG ratios and also be pro-inflammatory. Seems like a self contradictory assertion.