ISRIB
ISRIB, integrated stress response inhibitor
Written by Aaron CuhaReviewed Sep 2026
Also known as: trans-ISRIB, integrated stress response inhibitor
Unlike everything else in this batch, ISRIB is not an approved medicine anywhere and has never been given to a human in a registered trial. It reversed spatial memory deficits in old mice and in mice after traumatic brain injury, and that is the whole case.
Overview
This entry belongs in a batch of repurposed prescription drugs as the control case. The other five compounds here are licensed medicines with decades of human safety data being taken off label. ISRIB is not. It has no approval in any country, no registered clinical trial, and no published human pharmacokinetics. Anyone taking it is the experiment.
What it does is well characterised in cells and rodents. The integrated stress response is a conserved pathway in which several different stress sensors converge on phosphorylating one serine in the translation initiation factor eIF2 alpha, which throttles general protein synthesis. ISRIB reverses the downstream consequence of that phosphorylation by acting on eIF2B, the exchange factor, effectively releasing the brake on translation.
The results that made its reputation are memory results in mice. The original 2013 report found enhanced spatial and fear-associated learning in treated mice. In 2017 the same collaboration reported that ISRIB reversed hippocampal-dependent cognitive deficits in two traumatic brain injury models, including when given weeks after the injury. In 2020 it reversed spatial memory deficits and improved working memory in old mice, alongside restored neuronal electrophysiology, restored dendritic spine density and reduced interferon and T cell immune profiles in hippocampus.
Every one of those is a mouse. The ageing claim is one of them.
Mechanism of action
Binds and stabilises the decameric form of eIF2B, the guanine nucleotide exchange factor for eIF2, activating it and so antagonising the translational block imposed by phosphorylated eIF2 alpha. Because the integrated stress response is the convergence point for endoplasmic reticulum stress, viral double-stranded RNA, amino acid deprivation and haem deficiency, inhibiting it downstream affects all four branches at once. That is the appeal and it is also the reason to be careful: the integrated stress response is a protective adaptation, and the original report noted that ISRIB reduces the viability of cells subjected to chronic endoplasmic reticulum stress.
Reading the research record
There is no human evidence about ISRIB at all, which is why this page carries no human evidence section. Not weak human evidence, not surrogate human endpoints, none. No registered clinical trial of ISRIB exists on ClinicalTrials.gov as of September 2026, more than a decade after the founding paper. That is unusual for a compound with this much attention and it is informative: ISRIB has poor aqueous solubility, and the commercial effort has gone into successor molecules rather than into ISRIB itself.
The successor programme is worth knowing about, because it is the closest thing to a human readout. Fosigotifator, an eIF2B activator developed in the same target space and licensed from the academic group behind ISRIB, has entered clinical trials for vanishing white matter disease. Two of its registered studies, a phase 1 study and a study in major depressive disorder, are listed as terminated. None of that is evidence about ISRIB, and none of it is evidence about ageing.
One more thing belongs on the page. The integrated stress response exists because it is protective. The founding ISRIB paper itself reported reduced viability in cells under chronic endoplasmic reticulum stress on the drug. A compound that removes a stress brake will look like a cognitive enhancer in a memory test and like something else entirely in a tissue that needed the brake. No study has run long enough in a mammal to tell you which of those dominates over years.
The evidence, charted
Fig. 1 · evidence composition
0of 4 citations (0%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2013 to 2020, counted from the citation list on this page. The newest citation on file is from 2020, more than five years ago; the published record may have gone quiet.
Fig. 3 · legal status at a glance
US
Not approved
UK
Not approved
AU
Not approved
CA
Not approved
Not approved in any of the four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2013
Pharmacological brake-release of mRNA translation enhances cognitive memory
The paper that introduced ISRIB, from a cell-based screen for PERK signalling inhibitors. It reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and treated mice showed significant enhancement in spatial and fear-associated learning. The same paper reports that ISRIB reduces the viability of cells under chronic endoplasmic reticulum stress, which is the harm signal hiding in the founding result.
eLife - Animal2017
Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury
Traumatic brain injury persistently activated the integrated stress response in mice, and ISRIB reversed hippocampal-dependent cognitive deficits in two injury models, focal contusion and diffuse concussive injury, including when given weeks after the injury, with the benefit persisting after treatment stopped. Suppressed hippocampal long-term potentiation was fully restored. One author holds the ISRIB patent application, licensed to Calico.
Proceedings of the National Academy of Sciences - Animal2020
Small molecule cognitive enhancer reverses age-related memory decline in mice
The ageing result, and the only one. ISRIB reversed integrated stress response activation in the aged mouse brain, reversed spatial memory deficits and improved working memory in old mice, and in hippocampus restored intrinsic neuronal electrophysiological properties and spine density while reducing interferon and T cell mediated immune profiles. Memory endpoints, not lifespan or healthspan. Several authors disclose commercial interests in the compound class.
eLife - In vitro2015
Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response
The mechanistic paper establishing that ISRIB works by dimerising and activating eIF2B rather than by acting on the kinases upstream. This is why it blocks all four branches of the integrated stress response at once.
eLife
What users report
Self-reported experiences, not evidence. Nothing below was measured under controlled conditions, and reports like these cannot separate a real effect from placebo, from the training or diet change that accompanied it, or from what the product actually contained. They are here because knowing what people describe, including what goes wrong, is worth reading alongside the studies.
- Nootropic forum users describe subjective clarity and verbal fluency effects, usually from unverified powder of unknown purity dissolved in a solvent at home.
- Dosing discussed in those communities is extrapolated from mouse milligram per kilogram figures, a conversion that is wrong in principle and has no human pharmacokinetic data to anchor it.
- There is no community safety record worth the name, because the exposure base is small, unmonitored and self-reported.
Sources: Nootropic forums and Reddit. Uncontrolled self-report on an unapproved research chemical with no human trial. Included so readers know what circulates, not as evidence of anything.
Frequently asked questions
Is ISRIB approved anywhere?
No. It is not approved in any country for any indication, and as of September 2026 there is no registered clinical trial of ISRIB in humans. Every other compound on this page is a licensed medicine. This one is a research chemical.
Does ISRIB reverse age-related memory loss?
In old mice, one 2020 study reported reversal of spatial memory deficits and improved working memory, with restored hippocampal spine density and neuronal properties. That is the entire ageing evidence base. No human has been tested.
Why has nobody run a human trial after more than ten years?
ISRIB has poor aqueous solubility, which complicates formulation, and the commercial development went into successor eIF2B activators instead. One of those, fosigotifator, is in trials for vanishing white matter disease, with a phase 1 study and a depression study both listed as terminated.
Is it safe?
Nobody knows, and that is the accurate answer rather than a cautious one. There is no human safety data. The integrated stress response is a protective pathway, and the original paper reported that ISRIB reduces the viability of cells under chronic endoplasmic reticulum stress.
How does it compare to the other drugs in this group?
It does not compare, and that is the point of including it. Empagliflozin, lamivudine, danazol, ambroxol and rilmenidine all have human safety records from their licensed use, and none of them has human ageing evidence. ISRIB has neither.