ISRIB (integrated stress response inhibitor) is an experimental drug that reverses the effects of eIF2α phosphorylation with an IC50 of 5 nM. It was discovered in the laboratory of Peter Walter at the University of California, San Francisco (UCSF) through a semi-automated screening of a large library of small molecules by Carmela Sidrauski, who decided to pursue research on it. It has been shown to inhibit eIF2α phosphorylation-induced stress granule (SG) formation. Since eIF2α phosphorylation is known to be involved in memory formation, ISRIB was tested to see whether it would be active in vivo and was found to readily cross the blood-brain barrier, with a half-life of eight hours.
Subsequent testing in 2013 found ISRIB to produce significant nootropic effects in mice, as measured by enhancement of spatial and fear-associated learning in standard water-maze and conditioned environment tests.
The technology was licensed to Calico in 2015 and Sidrauski was hired to help find possible drugs based on ISRIB. She heads the laboratory in which it is being studied.
Testing in 2017 indicated the experimental drug improved the ability of brain-injured mice to learn and form memories on memory tests, thus appearing to reverse impairments from traumatic brain injury. ISRIB treatment also corrects spatial memory deficits and improves working memory in aged mice.
Further research on the drug by Sidrauski has shown that the molecule restored memory formation in mice months after traumatic brain injuries. It also has shown potential in treating neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s disease (also known as amyotrophic lateral sclerosis, or ALS). In mice, it has reduced age-related cognitive decline and given healthy mice improved memory. Research on ISRIB by Sidrauski continues at Calico.
In an Alzheimer’s animal model, a dose of ISRIB too high (5mg/kg) caused excessive mortality and the dose had to be lowered (Briggs et al, 2017). An effective, yet non-lethal dose and dosing schedule, has yet to be determined and may depend on the particular disease being treated. Whether long-term treatment with ISRIB is safe is also not yet determined. https://www.alzdiscovery.org/uploads/cognitive_vitality_media/ISRIB.pdf
"The molecule was well-tolerated in the animal studies described here, and did not elicit any relevant effects in a rat cardiovascular (CV) safety study; however, significant anomalies were observed in a dog CV model. This CV safety liability makes this particular molecule unsuitable for human dosing."
So basically, the mechanism of action is sound but it looks like they will have to tweak the drug to make it work in humans/ other animals, it is strange that this was not expended on in the article:
https://elifesciences.org/articles/42940
There is a report of one person who tried just two small doses of ISRIB (total of 15 mg intranasally) passing out and collapsing two days later. This is a young person with no previous history of passing out or having heart issues.
On going to the hospital, the cardiologist performed an ECG (electrocardiogram), and found the heart was out of whack. The heart rate was erratic, varying from normal to extremely low (20 bpm). Heart arrhythmias in the form of atrial fibrillation were diagnosed. Electric shock to the heart (cardioversion) was planned, to knock the heart back to a normal rhythm; but then the heart returned to normal rhythm on its own. On release from the hospital, no further heart problems were observed, and heart enzymes were fine, suggesting no permanent damage.
Another person who took 110 mg of ISRIB over 4 days (partly intranasally, partly orally dissolved in DMSO), reported getting some chest discomfort, modest chest pain, and some shortness of breath lasting several days, which appeared one week after their last dose of ISRIB. This person had no previous heart issues, and an ECG and ultrasound performed by a cardiologist 6 months prior showed a healthy heart.
Other people have reported a slow heart rate while on ISRIB.
There is also a report of a high-functioning autistic woman who suffered brain injuries as a child experiencing a short period of psychosis and hallucinations episode while taking ISRIB. She had experienced episodes of psychosis previously, but never with hallucinations. She previously had also taken ISRIB previously without such adverse effects.
The above reports come from a Telegram ISRIB group and a Discord ISRIB channel.
A compound called 2BAct, which works similarly to ISRIB, was found to cause significant cardiovascular anomalies in dogs.
To quote the paper:
The molecule was well-tolerated in the animal studies described here, and did not elicit any relevant effects in a rat cardiovascular (CV) safety study; however, significant anomalies were observed in a dog CV model. This CV safety liability makes this particular molecule unsuitable for human dosing.
Another paper found that the integrated stress response (ISR, which ISRIB inhibits) affects the heart. The paper states that the ISR regulates the autophagy and apoptosis (cell death) of cardiac progenitor cells. So taking ISRIB will have an effect on these cardiac cells.
And this paper says there is a connection between activating the ISR and arrhythmias. If there were a rebound effect on the ISR when you stop ISRIB, you might get higher levels of ISR after stopping, which might trigger arrhythmias. This rebound might explain why the heart issues experienced by the two people above only appeared some days after they stopped ISRIB.
In cell culture studies where ER-stress was artificially induced, 24 hours of ISRIB treatment in vitro accelerated cell death (Sidrauski et al, 2013). This suggests that in diseases characterized by increased ER stress, UPR or ISR modulators such as ISRIB might be toxic. Ref: here.
Conditions that involve endoplasmic reticulum (ER) stress include viral infection, type 2 diabetes, atherosclerosis, metabolic syndrome, cardiovascular diseases, obesity, and fatty liver disease. Ref: here.
ISRIB has never been tested on humans in any clinical trial, and although it can be bought at some research chemical and peptide suppliers, and is being researched by Google's Calico, to me, after learning more about ISRIB, it does not look like a safe substance to experiment with.
Indeed, ISRIB researcher Professor Susanna Rosi, who is exploring the potential benefits of ISRIB, stated "ISRIB is still far from being used to treat humans".
I was looking into ISRIB to see if it might be useful to help repair the mild brain damage I sustained from the viral encephalitis which triggered my ME/CFS; but after these reports of possible cardiac ill effects, I am not going to risk it.
Get more info from: https://forums.phoenixrising.me/threads/experimental-drug-reverses-cognitive-decline.82229/#post-2322604
https://www.reddit.com/r/Isrib/comments/lucfe4/you_all_really_need_to_read_this/
Intraperitoneal injection or IP injection is the injection of a substance into the peritoneum (body cavity). It is more often applied to animals than to humans.
The toxicity of dimethyl sulfoxide (DMSO) to mice was measured by giving ip doses in concentrations of 25, 50, 75, or 100%.
It was found that the LD50 increased somewhat as the concentration decreased, but the increase was significant only at the interval between 50 and 25%.
The LD50 values found for the above four concentrations were 15.4, 13.3, 11.9, and 10.9 g/kg, respectively.
https://www.sciencedirect.com/science/article/abs/pii/0041008X69900271
| DMSO Concentration | LD50 (g/kg) |
|---|---|
| 25 | 15.4 |
| 50 | 13.3 |
| 75 | 11.9 |
| 100 | 10.9 |
https://www.reddit.com/r/Isrib/comments/phjytd/poll_what_is_the_best_roa_for_isrib/
The solubility of trans-ISRIB in DMSO is approximately 2 mg/ml. trans-ISRIB is sparingly soluble in aqueous solutions.
ISRIB solution was made by dissolving 5 mg ISRIB in 2.5 mLs of 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, and 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 for up to 7 days 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
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 water bath 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 a 2.5 mg/kg dosage through i.p. injections. The vehicle solution consisted of 1 mL DMSO and 1 mL PEG400.
Start with 5 mg diluted with 3-5ml of DMSO. You MUST use DMSO or else it will not absorb into your body. IT WILL NOT WORK TRANSDERMALLY! Put your ISRIB and DMSO mixture (in something like a shot glass) surrounded by a larger container of boiling hot water to heat it (help it mix faster). Try to ensure that the solution is as transparent as possible. Then use the needle to puncture two holes (to stop it from exploding) into a fish oil capsule. Squeeze the oil out. Now draw up your ISRIB+DMSO and inject it into the capsule. Swallow, repeat. I have taken up 100mg of ISRIB at a time (about 30-40 fish oil caps). PEG400 was also used in the ISRIB study to dissolve ISRIB, so you could potentially use that, I don't have experience with it. DMSO is an absolute monster by itself.
https://www.reddit.com/r/Nootropics/comments/laose1/dihexa_a_new_route_of_administration_worth/
See https://scienceofparkinsons.com/2021/04/24/isrib/
Had a concussion November 2019. My eyes were out of sync, slowed reading speed and comprehension. Tried many experimental noots including isrib months back before the shop had fully established. Didn’t work any RoA I tried, my eyes miraculously corrected themselves on Monday following a week of migraine like forehead throbbing which restored my cramped peripheral vision; I thought to try the like 30-40mg left(unsure but a decent clump) snorted, noticed mild pressure at the concussion site a few hours later and mild tightness in my chest. Music started to sound really really good, right brain left brain working together again, visualisation, verbal fluency and working memory have clearly improved. https://www.reddit.com/r/Isrib/comments/n390hp/time_and_a_single_isrib_dose_healed_my_concussion/
I have heard mixed reports about insufflation, but the consensus appears to be that snorting is the least efficient method of ingesting ISRIB, and injection of ISRIB dissolved in DSMO seems to work the best. I took it orally for just over a week, and it vastly improved all aspects of cognition, but primarily memory. My dosage changed dramatically from day to day, but it still left me better than before. It truly is a miracle drug. https://www.reddit.com/r/Isrib/comments/our8ud/tbi_in_past_experimenting_w_insufflation_about/
Yep, ISRIB works perfectly orally without DMSO. It is the only way I’m consuming this stuff now. I’ve tried in rectally (solution ISRIB + DMSO + Glycerine (a little bit, because dmso rectally goes very painfully), before “infusing” it in my.... I’m using loperamide rectally because glycerine and dmso will hardly trying to go back)). Rectally it works good, better then orally without dmso (I’m a little bit scary about trying it orally with dmso.. dmso is so bad to drink this shit). I also tried in intravenously, solution ISRIB + DMSO (2mg isrib per 1ml dmso) and it was very painful, I was was screaming because of pain. Pure solution of dmso sucks, my veins were fucked up. Now I’m going to buy PEG-400 and then try the next solution intravenously: per 5mg ISRIB — 1ml DMSO + 1mg PEG-400. My friends from Russia have tried 50mg of ISRIB intravenously in 1 day in two passes. Then they had strongly hypomanic state, mad motivation, sleep for 5 hrs and so on. They said that ISRIB solution in PEG-400 + DMSO (1:1) were not painful. And it is good. I’ve also tried ISRIB intranasal. Can’t say exactly was it better than orally.. maybe yes, maybe no. I don’t know. One of my friends said that you can solute ISRIB in PEG-400 and consume it intranasal. Maybe. I’m thinking of synthesizing cyclodextrine complex with ISRIB. Maybe then (I suppose so), this complex will solute in water, so there would not be such problems with ISRIB consumption (it would be my own development). My typical dosage is about 15mg orally without DMSO. After 5 minutes I feel a strong surge of energy. I’m dosing it everyday for a week. Throughout this time, perhaps the most severe depressive episode of my life that had finally ended, I can live without kratom much longer (I am addicted for about year to kratom), almost without discomfort. The need for sleep decreased for about 30% and when I’m waking up, I feel a lot of energy. I never become tired, although I’m working hard in org chemistry lab and we are preparing a very huge science article about isoxazolines, and after work I have enough mental energy for studying. My memory and ability to perceive information significantly improved, my appetite increased twice. I need to eat a lot, because ISRIB allows the body to expend much more energy, correcting an evolutionarily resulting defect in the cellular system of protein synthesis (integrated response to a low stress, there is growing evidence of persistent, smoldering ISR activation in neurodegenerative diseases and conditions exhibiting memory consolidation defects, such as traumatic brain injury; but ISRIB can not antagonize the effects of high P-eIF2a levels (the result of ISR activation), induced by various viral infections, so you’ll not die due to coronavirus. However, ISRIB is not only the PERK (that is activated by different endoplasm. reticulum). It also inhibits GCN2 (that is activated by amino acid deprevation), HRI (activated by heme deprevation or in the presence of heavy metals) and PKR (activated by viral infections). ISRIB inhibits ISR, that means that eIF2 (eukaryotic initiation factor 2, wich participates in initiation of protein synthesis (translation)) becomes insensitive for his kinases which I have listed above. Isrib helps in killing agressive prostate cancer (https://pubmed.ncbi.nlm.nih.gov/29720449/). It helps with social anxiety (https://pubmed.ncbi.nlm.nih.gov/28584287/), normalize the behavioral and neuropsychological abnormalities in Down syndrome (https://pubmed.ncbi.nlm.nih.gov/31727829/), helps with diabetic hepatotoxity by antagonizing PERK-eIF2a-ATF4 pathway (https://pubmed.ncbi.nlm.nih.gov/30877037/), helps with methylglyoxal-induced pain (https://pubmed.ncbi.nlm.nih.gov/30157134/), supresses MEHMO syndrome mutation (https://pubmed.ncbi.nlm.nih.gov/31836389/) and so on, and so on. It may help with alzheimer disease, TBI, maybe parkinson syndrome, and with some types of cancer. One of my friends from Russia (now he is studying in UK) was one of the first guys that had tried this stuff. He had a brain trauma (automobile accident) in a childhood. Then he has hardly fucked up with an idea of repairing his brain. He analyzed his brain on MRT (I’ll show this photos) and a big part of PFC was totally fucked. After a course of ISRIB he scanned his brain one more time and all was good (don’t have the MRT photo, only a doctors conclusion, but it is russian language there). As for me, I can totally say. It's hard to judge my current state compared to pre-ISRIB... New baselines created all the time, so I don't really know where the bottom was compared to the new heights. it seems like anything that is somewhat less than what my current state seems like a horrible existence... I just need to go higher and higher... Does that make sense? I really do not give a single fuck about my body so long as my mind functions at a level that I am satisfied with. Also, I wonder if me snorting some IDRA-21 and ISRIB in combine before doing some drugs (like acid, alcohol, valium, weed, etc). Integrated response to low stress is, essentially, a limiter of our energy potential. Previously, for example, when there was a lack of food, people was turned on to save energy. Now, in the conditions of the modern world, such a function is not needed. Isrib allows you to consume more food and this, for a minute, is an evolutionary breakthrough. All evolutionary leaps have been associated with the ability to use more energy. This drug has enormous therapeutic potential, therefore further research in humans is required. https://pastebin.com/ZBTAj7gJ?fbclid=IwAR0rb-cuIlsZo_OjkZJ4KNdt0X2bSrWTniQAE8p-TIBtt0N8pkGK5Gpo31A