ISRIB to treat ME/CFS

mitoMAN

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ISRIB

Several members and I are hosting a 3rd Party Lab Analysis of an ISRIB Supplier! If you want to join, please PM me.

Taken From the Research Section:
https://forums.phoenixrising.me/threads/experimental-drug-reverses-cognitive-decline.82229/

Source: https://neurosciencenews.com/age-cognition-reversal-drug-17347/
Below is a partial list of these conditions, based on a recent review by Walter and colleague Mauro Costa-Mattioli of Baylor College of Medicine, which could potentially be treated with an ISR-resetting agent like ISRIB:

  • Frontotemporal Dementia
  • Alzheimer’s Disease
  • Amyotrophic Lateral Sclerosis (ALS)
  • Age-related Cognitive Decline
  • Multiple Sclerosis
  • Traumatic Brain Injury
  • Parkinson’s Disease
  • Down Syndrome
  • Vanishing White Matter Disorder
  • Prion Disease




Quoting member @Hip
Interesting how rapidly this drug ISRIB works (in mice): Drug Reverses Age-Related Mental Decline Within Days.

ISRIB treatment seems quite long-lasting too:
The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.
The safety of ISRIB looks good as well:
One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors, Walter says.

First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state, after which it can still respond normally to problems in individual cells.

Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form – against an aggressive viral infection, for example.
ISRIB stands for Integrated Stress Response (ISR) InhiBitor.



Here is some info I found on the integrated stress response (ISR).

Reading this makes me think an overactive ISR might play a role in ME/CFS, especially since the body activates the ISR in response to viral infection. The IST seems to be a kind of cell danger response, from what I can see.

When the ISR is triggered, it temporarily halts protein synthesis in the cell.

Obviously viruses which have entered a cell require protein synthesis to create copies of themselves, so if the body's ISR response kicks in and halts protein synthesis, then that will tend to stop viral replication.

The integrated stress response protects cells from a variety of harmful stressors by temporarily halting protein synthesis. However, chronic ISR activation has pathological consequences and is linked to several neurological disorders.
Source: here.


The integrated stress response can be triggered within a cell due to certain conditions. These can either be extrinsic or intrinsic factors.

Extrinsic factors include hypoxia, amino acid deprivation, glucose deprivation, viral infection and presence of oxidants.

The main intrinsic factor is endoplasmic reticulum stress due to the accumulation of unfolded proteins.
 
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mitoMAN

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Solubility:
Drug Administration. ISRIB solution was made by dissolving 5 mg ISRIB in 1 mL dimethyl sulfoxide (DMSO) (Fisher Scientific, D128-500) and 1 mL polyethylene glycol 400 (PEG400) (EMD Millipore, PX1286B-2). The solution was gently heated in a 40 °C waterbath and vortexed every 30 s until the solution became clear. The solution was kept in a warm environment throughout the experiment. Each solution was used for injections up to 4 d maximum. If the solution became visibly cloudy or precipitated, a new solution was prepared. ISRIB was delivered at 2.5 mg/kg dosage through i.p. injections. The vehicle solution consisted of 1 mL DMSO and 1 mL PEG400.




Solubility Data Solvent Max Conc. mg/mL Max Conc. mM Solubility DMSO 4.51 10 with gentle warming


pure DMSO would be enough it seems for 4.5mg/ml !
 

mitoMAN

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Another more complex solution:
ISRIB solution was made by dissolving 5 mg ISRIB in 2.5 mLs dimethyl sulfoxide (DMSO) (PanReac AppliChem, 191954.1611). The solution was gently heated in a 40°C water bath and vortexed every 30 s until the solution became clear. Next 1 mL of Tween 80 (Sigma Aldrich, P8074) was added, the solution was gently heated in a 40°C water bath and vortexed every 30 s until the solution became clear. Next, 10 mL of polyethylene glycol 400 (PEG400) (PanReac AppliChem, 142436.1611) solution was added gently heated in a 40°C water bath and vortexed every 30 s until the solution became clear. Finally, 36.5 mL of 5% dextrose (Hospira, RL-3040) was added. The solution was kept at room temperature throughout the experiment. Each solution was used for injections up to 7 day maximum. The vehicle solution consisted of the same chemical composition and concentration (DMSO, Tween 80, PEG400% and 5% dextrose). Stock ISRIB solution was at 0.1 mg/ml and injections were at 2.5 mg/kg. Each animal received an intraperitoneal injection of 2.5x their body weight.
 
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I checked my nootropics box and found that I still have 2 ISRIB vials (50mg each) that I bought from reachgenius. I had tried ISRIB on myself long time ago after I posted about it on reddit: https://www.reddit.com/r/Nootropics/comments/ef4jti
In my experience, I tried maybe 2-5mg dosage via DMSO, and as far as I remember, the name of the drug "integrated stress response inhibitor" pretty much describes the effect. For me it felt like strong anxiolytic, like the anxiety mechanism got disabled. My attention I remember was much better. But I stopped after maybe 3-4 attempts because I did not like the anxiolytics effect (which felt like I'm satisfied with everything). Also it felt pretty scary to be probably one of the first humans trying this (I did not find any other reports online on its effect on humans).
I think it can be a miracle for someone with GAD, but I don't want to make any claims, but it would be cool to see what happens on a person like that.

I can sell 1x50mg vial for 90€ + shipping from Europe.
 

Hip

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I checked my nootropics box and found that I still have 2 ISRIB vials (50mg each) that I bought from reachgenius. I had tried ISRIB on myself long time ago after I posted about it on reddit:
Interesting that ReachGenius no longer sell ISRIB. I wonder if that was due to poor sales, difficulty in obtaining ISRIB (unlikely since there are dozens of suppliers on Alibaba), or possibly because some people trying it reported adverse effects?
 

mitoMAN

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From @Hip

It might be an idea for ME/CFS patients to start with low doses of ISRIB. The integrated stress response (ISR) is used in cells to block viral infection, and if ME/CFS patients have a low-level viral infection in the cells of their brain, you would not want to inhibit the ISR suddenly and strongly with ISRIB, in case the viral infection springs back to life too quickly.

However, I read in an article that springing back to life is unlikely, as "ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form – against an aggressive viral infection, for example". Source: https://www.ucsf.edu/news/2020/12/419201/drug-reverses-age-related-mental-decline-within-days