ISRIB

updated

ISRIB (integrated stress response inhibitor) is a research compound sold for cognitive restoration after stress or injury and for memory enhancement. Its published work is cell studies, protein-structure work and rodent experiments from several laboratories, and no registered or published human study of ISRIB exists: ClinicalTrials.gov returned no study on 10 October 2026, and a PubMed query for ISRIB returned 258 records with none carrying a clinical publication type. The human trials in this field are of separate drugs, DNL343 and fosigotifator, and did not show slowing of ALS.

Integrated stress response inhibitor (eIF2B-binding bis-O-arylglycolamide)

  • ISRIB is PubChem CID 1011240, C22H24Cl2N2O4, molecular weight 451.3; three CAS numbers are listed among its synonyms and which belongs to which isomer is not resolved.
  • ISRIB reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM in cells, and binds eIF2B to antagonize phosphorylated eIF2 allosterically.
  • In two mouse models of traumatic brain injury, ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped.
  • DNL343, a different molecule from ISRIB, had a median disease rate ratio of 1.04 in the HEALEY ALS Platform Trial (249 randomized) and did not show slowing of ALS progression.
  • The ISRIB-like activators 2BAct and PRXS571 shortened survival in SOD1 G93A ALS mice, which is a result for those analogs and not for ISRIB itself.
  • A ClinicalTrials.gov query on 10 October 2026 returned no ISRIB study, and the ALSUntangled assessment found no clinical trials of ISRIB in any condition.

What is ISRIB, and what is its regulatory status?

ISRIB is a research compound, PubChem CID 1011240, that blocks the integrated stress response by binding eIF2B. It has no label and no registered study, and the clinical-stage drugs grouped with it, DNL343 and fosigotifator, are separate molecules.

ISRIB (integrated stress response inhibitor) is PubChem CID 1011240, C22H24Cl2N2O4, 451.3 g/mol, 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The synonyms list CAS 1597403-47-8, 548470-11-7 and 1597403-48-9, and the names trans-ISRIB, ISRIB (trans-isomer) and a cis-cyclohexane name. Which number belongs to which isomer is not resolved, so the stereochemistry of any vendor material should be confirmed. A 2016 structure-activity paper calls the class bis-O-arylglycolamides.

The clinical-stage molecules that get grouped with ISRIB are separate compounds: DNL343 (Denali), fosigotifator (ABBV-CLS-7262, AbbVie), and ISRIB-like compounds such as 2BAct and PRXS571. A 2026 medicinal chemistry paper says fosigotifator came from replacing the cyclohexyl core and side chains of ISRIB, through a truncated analogue (2BAct) and a prodrug step, so it is a descendant and not ISRIB. Nothing in the clinical record described below was run with ISRIB. No public record ties any vendor material to the studied compound.

On 10 October 2026 DailyMed returned no label for ISRIB, and ClinicalTrials.gov queries for ISRIB, integrated stress response inhibitor and eIF2B activator returned no studies. A 2025 paper states DNL343 is an investigational drug not approved by any health authority.

PubChem: ISRIB identity, isomers and CAS numbers, and what ISRIB is not

Chemical identity record

PubChem, National Library of Medicine. Compound summary for CID 1011240, 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide (ISRIB).

ISRIB (integrated stress response inhibitor) is PubChem CID 1011240, C22H24Cl2N2O4, 451.3 g/mol, IUPAC name 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The synonyms list CAS 1597403-47-8, 548470-11-7 and 1597403-48-9, and the names trans-ISRIB, ISRIB (trans-isomer) and a cis-cyclohexane name; which number belongs to which isomer was not resolved. A 2016 structure-activity paper calls the class bis-O-arylglycolamides (PMID 26789650). The clinical-stage molecules that get grouped with ISRIB are separate compounds: DNL343 (Denali), fosigotifator (ABBV-CLS-7262, AbbVie), and ISRIB-like compounds such as 2BAct and PRXS571. A 2026 medicinal chemistry paper says fosigotifator came from replacing the cyclohexyl core and side chains of ISRIB, through a truncated analogue (2BAct) and a prodrug step, so it is a descendant and not ISRIB. Nothing in the clinical record on this page was run with ISRIB.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, free form
Follow-up
Not applicable
Study design
Chemical database record; original chemistry papers
Funding
not stated in the source

Identity record only. The stereochemistry of any vendor material should be confirmed, and no public record ties any vendor material to the studied compound.

Read the original source
Label and registry searches, 10 October 2026: no label, no ISRIB study

Regulatory record

U.S. Food and Drug Administration (DailyMed label search) and ClinicalTrials.gov. Searches for ISRIB, integrated stress response inhibitor and eIF2B activator, run 10 October 2026.

A ClinicalTrials.gov query for ISRIB run on 10 October 2026 returned no studies, nor did queries for 'integrated stress response' inhibitor and 'eIF2B activator'. DailyMed returned no label for ISRIB. No registered ISRIB trial was found.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated label and registry search
Funding
not stated in the source

An absence finding as of 10 October 2026. It covers United States label and registry records only.

Read the original source
Different drug: DNL343 in 249 people with ALS, rate ratio 1.04, no slowing

Randomized controlled trial

Paganoni S et al. JAMA Netw Open. 2026;9(9):e2634809. PMID 42771346.

Denali's eIF2B activator DNL343 was tested in Phase 1 and Phase 1b randomized trials in healthy and ALS participants (NCT04268784 and NCT05006352 per the paper), where it showed extensive CSF distribution, was generally well tolerated, and reduced ISR biomarkers in blood cells and CSF (PMID 40825784). In the HEALEY ALS Platform Trial regimen (NCT05842941, 74 US centers, 24 weeks, 200 mg per day), 249 participants were randomized to DNL343 (n = 186) or regimen-specific placebo (n = 63), analyzed with 139 shared placebo participants; the median disease rate ratio was 1.04 (95% credible interval 0.83 to 1.32, probability of rate ratio below 1 of 0.37), secondary measures did not differ, adverse event rates were similar, and the authors conclude 200 mg per day did not show evidence of slowing ALS progression. A 2025 paper states DNL343 is an investigational drug not approved by any health authority.

Participants / model
People with ALS; healthy participants
Treatment
Oral DNL343, a different molecule from ISRIB
Follow-up
24 weeks in the HEALEY ALS Platform Trial regimen
Study design
Randomized clinical trial and early-phase trial report, of an ISRIB-like drug in motor neuron disease
Funding
not stated in the source

This is a different molecule in a motor neuron disease, and it says nothing about memory or about ISRIB itself.

Read the original source

What did the mouse and rat studies find?

In mice and rats ISRIB improved learning, reversed memory deficits in old mice, and reversed hippocampal-dependent deficits after brain injury, including when given weeks later. All of it is rodent and cell work from several laboratories, with doses and routes missing from most abstracts, and ISRIB has not been tested in a registered or published human study.

A cell-based screen for inhibitors of PERK signaling found ISRIB, which reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and ISRIB-treated mice showed significant enhancement of spatial and fear-associated learning; dose and route are not in the abstract. In old mice ISRIB reversed integrated stress response (ISR) activation in the brain (lower ATF4 and phosphorylated eIF2), reversed spatial memory deficits, ameliorated working memory, rescued intrinsic neuronal electrophysiology, restored spine density, and reduced interferon and T cell immune profiles in the hippocampus. That abstract gives no dose, route or schedule.

In two mouse models of traumatic brain injury (focal contusion and diffuse concussive injury), ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped; long-term potentiation, suppressed by injury, was fully restored. In mice with mild repetitive head injury, which increased risk-taking behavior in males but not females, ISRIB given weeks later reversed the behavior and restored cell-specific synaptic function.

In adult rats exposed to ethanol in adolescence, ISRIB improved spatial learning and memory impairment and neuronal damage. In a rat model of vascular cognitive impairment (permanent bilateral carotid occlusion), ISRIB microinjected into the hippocampal dentate gyrus improved spatial, working and recognition memory and restored synaptic markers, which is local brain delivery and not a systemic route. In mice with a tibial fracture under isoflurane, a model of postoperative cognitive dysfunction, ISRIB lowered ISR and oxidative stress markers in the hippocampus and ameliorated cognitive dysfunction.

The stress half of the claim is tested in one mouse study of chronic restraint stress, where 2 weeks of ISRIB improved depression-like behavior and reversed hypothalamic-pituitary-adrenal axis hyperactivity in male mice, and in females improved anhedonia but not forced-swim or tail-suspension immobility. That measures mood-like behavior with a sex difference, not memory.

Krukowski K, Rosi S and Walter P are authors on the aged-mouse and injury papers, and the injury papers' conflict statements say Walter P holds a patent on ISRIB licensed to Calico. Doses and routes are not in most of these abstracts.

2013 discovery from a PERK cell screen (IC50 5 nM), better learning in mice, and the 2021 eIF2B binding structures

Animal study

Sidrauski C et al. Elife. 2013;2:e00498. PMID 23741617.

A cell-based screen for inhibitors of PERK signaling found ISRIB, which reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and ISRIB-treated mice showed significant enhancement of spatial and fear-associated learning; dose and route are not in the abstract. The 2013 abstract also reports that ISRIB reduces the viability of cells subjected to PERK activation by chronic ER stress. A 2021 paper shows ISRIB binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, with cryo-EM structures, so the mechanism is well defined in vitro (PMID 33220178).

Participants / model
Cell lines; mice
Treatment
Cell assays; the in vivo route is not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical studies
Funding
not stated in the source

Discovery paper plus a paper on the eIF2B binding structures. Neither gives an in vivo dose or route in its abstract.

Read the original source
Old mice: spatial and working memory, spine density, hippocampal physiology

Animal study

Krukowski K et al. Elife. 2020;9. PMID 33258451.

ISRIB reversed ISR activation in the brain of old mice (lower ATF4 and phosphorylated eIF2), reversed spatial memory deficits, ameliorated working memory, rescued intrinsic neuronal electrophysiology, restored spine density, and reduced interferon and T cell immune profiles in the hippocampus. The abstract gives no dose, route or schedule.

Participants / model
Old mice
Treatment
ISRIB; dose, route and schedule not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

Krukowski K, Rosi S and Walter P are authors here and on the injury papers, where the conflict statements say Walter P holds a patent on ISRIB licensed to Calico; this record shows no conflict statement.

Read the original source
Brain injury, head injury, postoperative and vascular models; one chronic stress study

Animal study

Chou A et al. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. PMID 28696288.

In two mouse models of traumatic brain injury (focal contusion and diffuse concussive injury), ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped; long-term potentiation, suppressed by injury, was fully restored. In mice with mild repetitive head injury, which increased risk-taking behavior in males but not females, ISRIB given weeks later reversed the behavior and restored cell-specific synaptic function (PMID 31884883). In adult rats exposed to ethanol in adolescence, ISRIB improved spatial learning and memory impairment and neuronal damage (PMID 39142353), and in a rat model of vascular cognitive impairment (permanent bilateral carotid occlusion), ISRIB microinjected into the hippocampal dentate gyrus improved spatial, working and recognition memory and restored synaptic markers (PMID 41380823), which is local brain delivery and not a systemic route. In mice with a tibial fracture under isoflurane, a model of postoperative cognitive dysfunction, ISRIB lowered ISR and oxidative stress markers in the hippocampus and ameliorated cognitive dysfunction (PMID 36212697). In one mouse study of chronic restraint stress, 2 weeks of ISRIB improved depression-like behavior and reversed hypothalamic-pituitary-adrenal axis hyperactivity in male mice, and in females improved anhedonia but not forced-swim or tail-suspension immobility (PMID 38942086).

Participants / model
Mice with traumatic brain injury; mice with repetitive head injury; mice with postoperative cognitive dysfunction or chronic restraint stress; rats
Treatment
ISRIB; not stated in most abstracts, microinjection into the dentate gyrus in the rat vascular study
Follow-up
Treatment given weeks after injury in the mouse injury studies; 2 weeks in the restraint stress study
Study design
Original preclinical studies
Funding
not stated in the source

Results come from several laboratories, all in rodents. The chronic restraint stress result measures mood-like behavior with a sex difference, not memory, and is not used for the memory claim. Doses and routes are not in most abstracts.

Read the original source

How does ISRIB act on the integrated stress response?

ISRIB binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, which cryo-EM structures show, so its mechanism is well defined in cells. In prion-diseased mice it restored global translation only partially, which the authors say spares protective stress responses.

ISRIB came out of a cell-based screen for inhibitors of PERK signaling and reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM. A 2021 paper shows it binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, with cryo-EM structures. The 2013 abstract also reports that ISRIB reduces the viability of cells subjected to PERK activation by chronic ER stress.

In old mice ISRIB lowered ATF4 and phosphorylated eIF2 in the brain. In prion-diseased mice it gave neuroprotection with only partial restoration of global translation, which the authors say spares protective stress responses in secretory tissue, in contrast to the PERK inhibitor GSK2606414 that was toxic to the pancreas.

The pathway also has protective roles. In cells ISRIB impaired degradation of proteins by the ubiquitin-proteasome system during proteotoxic stress, and the authors flag a risk that blocking the pathway compromises recovery of protein homeostasis.

2013 discovery from a PERK cell screen (IC50 5 nM), better learning in mice, and the 2021 eIF2B binding structures

Animal study

Sidrauski C et al. Elife. 2013;2:e00498. PMID 23741617.

A cell-based screen for inhibitors of PERK signaling found ISRIB, which reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and ISRIB-treated mice showed significant enhancement of spatial and fear-associated learning; dose and route are not in the abstract. The 2013 abstract also reports that ISRIB reduces the viability of cells subjected to PERK activation by chronic ER stress. A 2021 paper shows ISRIB binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, with cryo-EM structures, so the mechanism is well defined in vitro (PMID 33220178).

Participants / model
Cell lines; mice
Treatment
Cell assays; the in vivo route is not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical studies
Funding
not stated in the source

Discovery paper plus a paper on the eIF2B binding structures. Neither gives an in vivo dose or route in its abstract.

Read the original source
Old mice: spatial and working memory, spine density, hippocampal physiology

Animal study

Krukowski K et al. Elife. 2020;9. PMID 33258451.

ISRIB reversed ISR activation in the brain of old mice (lower ATF4 and phosphorylated eIF2), reversed spatial memory deficits, ameliorated working memory, rescued intrinsic neuronal electrophysiology, restored spine density, and reduced interferon and T cell immune profiles in the hippocampus. The abstract gives no dose, route or schedule.

Participants / model
Old mice
Treatment
ISRIB; dose, route and schedule not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

Krukowski K, Rosi S and Walter P are authors here and on the injury papers, where the conflict statements say Walter P holds a patent on ISRIB licensed to Calico; this record shows no conflict statement.

Read the original source
Prion mice without pancreatic toxicity; proteasome impairment in cells; analogs worsened ALS mice

Animal study

Marlin E et al. Br J Pharmacol. 2024;181(3):495-508. PMID 37823684.

In prion-diseased mice ISRIB gave neuroprotection with no adverse effect on the pancreas, and only partial restoration of global translation, which the authors say spares protective stress responses in secretory tissue, in contrast to the PERK inhibitor GSK2606414 that was toxic to the pancreas (PMID 25741597). In cell experiments ISRIB impaired degradation of proteins by the cytosolic ubiquitin-proteasome system during proteotoxic stress, with accumulation comparable to a proteasome inhibitor, and the authors flag a risk that ISR inhibition compromises recovery of protein homeostasis (PMID 39379572). The two ISRIB-like eIF2B activators 2BAct and PRXS571 anticipated disease onset, aggravated muscle denervation and motor neuron death, and shortened survival in SOD1 G93A ALS mice, which the authors say reveals toxicity eIF2B activators may display in ALS patients. A 2025 narrative review says ISRIB's long-term safety is open and that rumors suggest efficacy versus safety may be compromised by side effects (PMID 38757325).

Participants / model
Prion-infected mice; cell lines; SOD1 G93A mice; review
Treatment
Not stated in the abstracts
Follow-up
not stated in the source
Study design
Original preclinical studies; review abstract
Funding
not stated in the source

The ALS mouse results are for the analogs and for ALS mice and do not show that ISRIB itself is harmful in people; they show the pathway has a protective role under some stresses.

Read the original source

What did trials of ISRIB-like drugs find?

Two clinical-stage drugs that act on the same pathway, DNL343 and fosigotifator, did not show slowing of ALS progression, but they are different molecules from ISRIB and tested a motor neuron disease, not memory. They neither support nor refute any ISRIB claim.

Denali's eIF2B activator DNL343 was tested in Phase 1 and Phase 1b randomized trials in healthy and ALS participants, where it showed extensive CSF distribution, was generally well tolerated, and reduced ISR biomarkers in blood cells and CSF. In the HEALEY ALS Platform Trial regimen (74 US centers, 24 weeks, 200 mg per day), 249 participants were randomized to DNL343 (n = 186) or regimen-specific placebo (n = 63) and analyzed with 139 shared placebo participants. The median disease rate ratio was 1.04 (95% credible interval 0.83 to 1.32, probability of rate ratio below 1 of 0.37), secondary measures did not differ, adverse event rates were similar, and the authors conclude 200 mg per day did not show evidence of slowing ALS progression.

ClinicalTrials.gov lists a fosigotifator HEALEY ALS regimen, NCT05740813 (Phase 2 and 3, 310 participants enrolled, two oral doses against placebo for 24 weeks, results posted on the registry). The two posted primary-outcome analyses give disease rate ratios of 1.06 (confidence interval 0.850 to 1.324) and 0.96 (0.753 to 1.220), which does not show slowing, and no peer-reviewed report was found in PubMed. Other records include a vanishing white matter disease study (recruiting), a Phase 1b in major depressive disorder (20 enrolled, terminated, no results posted) and an ALS Phase 1 (31 enrolled, terminated). The posted figures are registry entries and the full results tables were not read.

These are different molecules in a motor neuron disease. DNL343 and fosigotifator are not ISRIB, and nothing in these trials was run with ISRIB.

Different drug: DNL343 in 249 people with ALS, rate ratio 1.04, no slowing

Randomized controlled trial

Paganoni S et al. JAMA Netw Open. 2026;9(9):e2634809. PMID 42771346.

Denali's eIF2B activator DNL343 was tested in Phase 1 and Phase 1b randomized trials in healthy and ALS participants (NCT04268784 and NCT05006352 per the paper), where it showed extensive CSF distribution, was generally well tolerated, and reduced ISR biomarkers in blood cells and CSF (PMID 40825784). In the HEALEY ALS Platform Trial regimen (NCT05842941, 74 US centers, 24 weeks, 200 mg per day), 249 participants were randomized to DNL343 (n = 186) or regimen-specific placebo (n = 63), analyzed with 139 shared placebo participants; the median disease rate ratio was 1.04 (95% credible interval 0.83 to 1.32, probability of rate ratio below 1 of 0.37), secondary measures did not differ, adverse event rates were similar, and the authors conclude 200 mg per day did not show evidence of slowing ALS progression. A 2025 paper states DNL343 is an investigational drug not approved by any health authority.

Participants / model
People with ALS; healthy participants
Treatment
Oral DNL343, a different molecule from ISRIB
Follow-up
24 weeks in the HEALEY ALS Platform Trial regimen
Study design
Randomized clinical trial and early-phase trial report, of an ISRIB-like drug in motor neuron disease
Funding
not stated in the source

This is a different molecule in a motor neuron disease, and it says nothing about memory or about ISRIB itself.

Read the original source
Different drug: fosigotifator in 310 people with ALS, posted rate ratios near 1, no peer-reviewed report found

Trial registry record

ClinicalTrials.gov. NCT05740813. HEALEY ALS Platform Trial regimen of fosigotifator (ABBV-CLS-7262), Phase 2 and 3, 310 participants enrolled, with other fosigotifator records NCT05757141, NCT06618118 and NCT04948645.

NCT05740813 is a HEALEY ALS regimen (Phase 2 and 3, 310 participants enrolled, start 2023-03-23, primary completion 2024-10-03, two oral doses against placebo for 24 weeks, results posted on the registry). The two posted primary-outcome analyses give disease rate ratios of 1.06 (confidence interval 0.850 to 1.324) and 0.96 (0.753 to 1.220), which does not show slowing. No peer-reviewed report was found in PubMed; a query on the drug names returned the chemistry paper only. Other records are an open-label exploratory study in vanishing white matter disease (NCT05757141, 50 participants estimated, recruiting), a Phase 1b in major depressive disorder (NCT06618118, 20 enrolled, terminated, no results posted), an ALS Phase 1 (NCT04948645, 31 enrolled, terminated), and several healthy-volunteer pharmacology studies.

Participants / model
People with ALS; people with vanishing white matter disease or major depressive disorder; healthy volunteers
Treatment
Oral fosigotifator, a prodrug-derived analog and not ISRIB
Follow-up
24 weeks in the HEALEY ALS regimen; start 2023-03-23, primary completion 2024-10-03
Study design
Registry records of Phase 1, Phase 1b, exploratory and Phase 2 and 3 studies
Funding
not stated in the source

The posted figures are registry entries and the full results tables were not read. The drug is a prodrug-derived analog, not ISRIB. The results should be compared with a peer-reviewed report when one appears.

Read the original source
PubChem: ISRIB identity, isomers and CAS numbers, and what ISRIB is not

Chemical identity record

PubChem, National Library of Medicine. Compound summary for CID 1011240, 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide (ISRIB).

ISRIB (integrated stress response inhibitor) is PubChem CID 1011240, C22H24Cl2N2O4, 451.3 g/mol, IUPAC name 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The synonyms list CAS 1597403-47-8, 548470-11-7 and 1597403-48-9, and the names trans-ISRIB, ISRIB (trans-isomer) and a cis-cyclohexane name; which number belongs to which isomer was not resolved. A 2016 structure-activity paper calls the class bis-O-arylglycolamides (PMID 26789650). The clinical-stage molecules that get grouped with ISRIB are separate compounds: DNL343 (Denali), fosigotifator (ABBV-CLS-7262, AbbVie), and ISRIB-like compounds such as 2BAct and PRXS571. A 2026 medicinal chemistry paper says fosigotifator came from replacing the cyclohexyl core and side chains of ISRIB, through a truncated analogue (2BAct) and a prodrug step, so it is a descendant and not ISRIB. Nothing in the clinical record on this page was run with ISRIB.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, free form
Follow-up
Not applicable
Study design
Chemical database record; original chemistry papers
Funding
not stated in the source

Identity record only. The stereochemistry of any vendor material should be confirmed, and no public record ties any vendor material to the studied compound.

Read the original source

Does ISRIB restore cognition after stress or injury?

In mice and rats, memory and cognition after injury and in old age improved with ISRIB, and in no person. The stress half of the claim rests on one mouse study of mood-like behavior, and the trials of ISRIB-like drugs in ALS neither support nor refute it.

Sellers describe cognitive restoration after stress or injury and memory enhancement. The memory and injury parts are supported in mice and rats by results from more than one laboratory, including old mice, two brain injury models, repetitive head injury, ethanol exposure, vascular cognitive impairment and postoperative cognitive dysfunction. The stress part is tested in one chronic restraint stress mouse study that measured depression-like behavior and anhedonia with a sex difference, not memory.

No person has been given ISRIB in a registered or published study. A ClinicalTrials.gov query for ISRIB on 10 October 2026 returned no studies, and a PubMed query for ISRIB returned 258 records, with none carrying the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study or phase I or II clinical trial. A broader human-terms query returned 163 records, and the 40 top-ranked titles were cell, animal, protein-structure or review papers; the one human-patient report is the ALSUntangled assessment of self-reported use, which could not be confirmed. The 2025 safety review says news of clinical trials has circulated without published information.

The human evidence in this field comes from analogs, which are different molecules tested in ALS, and it supports nothing about memory in people.

Old mice: spatial and working memory, spine density, hippocampal physiology

Animal study

Krukowski K et al. Elife. 2020;9. PMID 33258451.

ISRIB reversed ISR activation in the brain of old mice (lower ATF4 and phosphorylated eIF2), reversed spatial memory deficits, ameliorated working memory, rescued intrinsic neuronal electrophysiology, restored spine density, and reduced interferon and T cell immune profiles in the hippocampus. The abstract gives no dose, route or schedule.

Participants / model
Old mice
Treatment
ISRIB; dose, route and schedule not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

Krukowski K, Rosi S and Walter P are authors here and on the injury papers, where the conflict statements say Walter P holds a patent on ISRIB licensed to Calico; this record shows no conflict statement.

Read the original source
Brain injury, head injury, postoperative and vascular models; one chronic stress study

Animal study

Chou A et al. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. PMID 28696288.

In two mouse models of traumatic brain injury (focal contusion and diffuse concussive injury), ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped; long-term potentiation, suppressed by injury, was fully restored. In mice with mild repetitive head injury, which increased risk-taking behavior in males but not females, ISRIB given weeks later reversed the behavior and restored cell-specific synaptic function (PMID 31884883). In adult rats exposed to ethanol in adolescence, ISRIB improved spatial learning and memory impairment and neuronal damage (PMID 39142353), and in a rat model of vascular cognitive impairment (permanent bilateral carotid occlusion), ISRIB microinjected into the hippocampal dentate gyrus improved spatial, working and recognition memory and restored synaptic markers (PMID 41380823), which is local brain delivery and not a systemic route. In mice with a tibial fracture under isoflurane, a model of postoperative cognitive dysfunction, ISRIB lowered ISR and oxidative stress markers in the hippocampus and ameliorated cognitive dysfunction (PMID 36212697). In one mouse study of chronic restraint stress, 2 weeks of ISRIB improved depression-like behavior and reversed hypothalamic-pituitary-adrenal axis hyperactivity in male mice, and in females improved anhedonia but not forced-swim or tail-suspension immobility (PMID 38942086).

Participants / model
Mice with traumatic brain injury; mice with repetitive head injury; mice with postoperative cognitive dysfunction or chronic restraint stress; rats
Treatment
ISRIB; not stated in most abstracts, microinjection into the dentate gyrus in the rat vascular study
Follow-up
Treatment given weeks after injury in the mouse injury studies; 2 weeks in the restraint stress study
Study design
Original preclinical studies
Funding
not stated in the source

Results come from several laboratories, all in rodents. The chronic restraint stress result measures mood-like behavior with a sex difference, not memory, and is not used for the memory claim. Doses and routes are not in most abstracts.

Read the original source
PubMed, 10 October 2026: 258 records, none with a clinical publication type

PubMed search record

PubMed search run 10 October 2026: ISRIB[tiab], with follow-up queries adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study or phase I or II clinical trial, and a broader human-terms query.

A PubMed query run on 10 October 2026 for ISRIB[tiab] returned 258 records, and adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study, or phase I or II clinical trial returned 0 records. A broader human-terms query returned 163 records, and the 40 top-ranked titles were screened and were cell, animal, protein-structure or review papers; the one human-patient report is the ALSUntangled assessment of self-reported use, which could not be confirmed. The 2025 safety review says news of clinical trials has circulated without published information (PMID 38757325), and no registered ISRIB trial was found. ISRIB is a research compound with human use limited to self-reported anecdote in the records reviewed, and the human evidence in this field comes from analogs.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated literature search
Funding
not stated in the source

An absence finding as of 10 October 2026, not proof that no unpublished or unindexed work exists. Only the 40 top-ranked titles of the broader query were screened.

Read the original source
Label and registry searches, 10 October 2026: no label, no ISRIB study

Regulatory record

U.S. Food and Drug Administration (DailyMed label search) and ClinicalTrials.gov. Searches for ISRIB, integrated stress response inhibitor and eIF2B activator, run 10 October 2026.

A ClinicalTrials.gov query for ISRIB run on 10 October 2026 returned no studies, nor did queries for 'integrated stress response' inhibitor and 'eIF2B activator'. DailyMed returned no label for ISRIB. No registered ISRIB trial was found.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated label and registry search
Funding
not stated in the source

An absence finding as of 10 October 2026. It covers United States label and registry records only.

Read the original source
ISRIB solubility, self-reported use and a topical cream; no ISRIB trials in any condition

Case report

Mascias Cadavid J et al. Amyotroph Lateral Scler Frontotemporal Degener. 2025;26(7-8):821-824. PMID 40762148.

The 2026 fosigotifator paper states that ISRIB's poor solubility limits absorption and advancement, and that the truncated analogue 2BAct had better solubility but cardiovascular effects in higher species limited its progress (PMID 42153306). The ALSUntangled assessment (2025) says questions about ISRIB's solubility and bioavailability have arisen, that a small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects that the reviewers could not confirm independently, and that there are no clinical trials evaluating ISRIB in any condition; it concludes there is not enough evidence to endorse its use for ALS. A 2024 formulation paper builds a topical cream of ISRIB for chemical-injury skin damage and reports delivery into skin with no detectable systemic exposure (PMID 39244069). No ISRIB pharmacokinetic figure (half-life, bioavailability or brain level) appears in the abstracts read.

Participants / model
Human patients (self-reports); formulation experiments
Treatment
Oral self-use reports; topical cream
Follow-up
not stated in the source
Study design
Expert assessment of self-reported use and the literature (ALSUntangled), a medicinal chemistry paper and a formulation paper; not a clinical study
Funding
not stated in the source

Anecdote that the reviewers could not confirm, not a study. It is the only report of human use of ISRIB itself in the records reviewed.

Read the original source

What is known about the safety of ISRIB?

No human safety data exist for ISRIB: no registered or published study has given it to people, and its human use is limited to self-reports that could not be confirmed. Cautions come from cells, prion mice and ISRIB-like drugs in ALS mice, a 2025 review calls its long-term safety open, and poor solubility limits absorption.

No registered or published study has given ISRIB to people. The ALSUntangled assessment (2025) says a small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects that the reviewers could not confirm, that there are no clinical trials evaluating ISRIB in any condition, and that there is not enough evidence to endorse its use for ALS.

In prion-diseased mice ISRIB gave neuroprotection with no adverse effect on the pancreas, in contrast to the PERK inhibitor GSK2606414 that was toxic to the pancreas. In cell experiments ISRIB impaired degradation of proteins by the cytosolic ubiquitin-proteasome system during proteotoxic stress, with accumulation comparable to a proteasome inhibitor, and the authors flag a risk that ISR inhibition compromises recovery of protein homeostasis.

The two ISRIB-like eIF2B activators 2BAct and PRXS571 anticipated disease onset, aggravated muscle denervation and motor neuron death, and shortened survival in SOD1 G93A ALS mice, which the authors say reveals toxicity eIF2B activators may display in ALS patients. Those results are for the analogs and for ALS mice and do not show that ISRIB itself is harmful in people; they show that the pathway has a protective role under some stresses. A 2026 paper adds that the analogue 2BAct had cardiovascular effects in higher species that limited its progress.

A 2025 narrative review says ISRIB's long-term safety is open and that rumors suggest efficacy versus safety may be compromised by side effects. A 2026 paper states ISRIB's poor solubility limits absorption, and no ISRIB pharmacokinetic figure (half-life, bioavailability or brain level) appears in the abstracts read. A 2024 formulation paper reports a topical cream delivering ISRIB into skin with no detectable systemic exposure.

Product identity is a separate concern: the stereochemistry and CAS number of vendor material should be confirmed, and no public record ties vendor material to the studied compound.

PubMed, 10 October 2026: 258 records, none with a clinical publication type

PubMed search record

PubMed search run 10 October 2026: ISRIB[tiab], with follow-up queries adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study or phase I or II clinical trial, and a broader human-terms query.

A PubMed query run on 10 October 2026 for ISRIB[tiab] returned 258 records, and adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study, or phase I or II clinical trial returned 0 records. A broader human-terms query returned 163 records, and the 40 top-ranked titles were screened and were cell, animal, protein-structure or review papers; the one human-patient report is the ALSUntangled assessment of self-reported use, which could not be confirmed. The 2025 safety review says news of clinical trials has circulated without published information (PMID 38757325), and no registered ISRIB trial was found. ISRIB is a research compound with human use limited to self-reported anecdote in the records reviewed, and the human evidence in this field comes from analogs.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated literature search
Funding
not stated in the source

An absence finding as of 10 October 2026, not proof that no unpublished or unindexed work exists. Only the 40 top-ranked titles of the broader query were screened.

Read the original source
Prion mice without pancreatic toxicity; proteasome impairment in cells; analogs worsened ALS mice

Animal study

Marlin E et al. Br J Pharmacol. 2024;181(3):495-508. PMID 37823684.

In prion-diseased mice ISRIB gave neuroprotection with no adverse effect on the pancreas, and only partial restoration of global translation, which the authors say spares protective stress responses in secretory tissue, in contrast to the PERK inhibitor GSK2606414 that was toxic to the pancreas (PMID 25741597). In cell experiments ISRIB impaired degradation of proteins by the cytosolic ubiquitin-proteasome system during proteotoxic stress, with accumulation comparable to a proteasome inhibitor, and the authors flag a risk that ISR inhibition compromises recovery of protein homeostasis (PMID 39379572). The two ISRIB-like eIF2B activators 2BAct and PRXS571 anticipated disease onset, aggravated muscle denervation and motor neuron death, and shortened survival in SOD1 G93A ALS mice, which the authors say reveals toxicity eIF2B activators may display in ALS patients. A 2025 narrative review says ISRIB's long-term safety is open and that rumors suggest efficacy versus safety may be compromised by side effects (PMID 38757325).

Participants / model
Prion-infected mice; cell lines; SOD1 G93A mice; review
Treatment
Not stated in the abstracts
Follow-up
not stated in the source
Study design
Original preclinical studies; review abstract
Funding
not stated in the source

The ALS mouse results are for the analogs and for ALS mice and do not show that ISRIB itself is harmful in people; they show the pathway has a protective role under some stresses.

Read the original source
ISRIB solubility, self-reported use and a topical cream; no ISRIB trials in any condition

Case report

Mascias Cadavid J et al. Amyotroph Lateral Scler Frontotemporal Degener. 2025;26(7-8):821-824. PMID 40762148.

The 2026 fosigotifator paper states that ISRIB's poor solubility limits absorption and advancement, and that the truncated analogue 2BAct had better solubility but cardiovascular effects in higher species limited its progress (PMID 42153306). The ALSUntangled assessment (2025) says questions about ISRIB's solubility and bioavailability have arisen, that a small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects that the reviewers could not confirm independently, and that there are no clinical trials evaluating ISRIB in any condition; it concludes there is not enough evidence to endorse its use for ALS. A 2024 formulation paper builds a topical cream of ISRIB for chemical-injury skin damage and reports delivery into skin with no detectable systemic exposure (PMID 39244069). No ISRIB pharmacokinetic figure (half-life, bioavailability or brain level) appears in the abstracts read.

Participants / model
Human patients (self-reports); formulation experiments
Treatment
Oral self-use reports; topical cream
Follow-up
not stated in the source
Study design
Expert assessment of self-reported use and the literature (ALSUntangled), a medicinal chemistry paper and a formulation paper; not a clinical study
Funding
not stated in the source

Anecdote that the reviewers could not confirm, not a study. It is the only report of human use of ISRIB itself in the records reviewed.

Read the original source
PubChem: ISRIB identity, isomers and CAS numbers, and what ISRIB is not

Chemical identity record

PubChem, National Library of Medicine. Compound summary for CID 1011240, 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide (ISRIB).

ISRIB (integrated stress response inhibitor) is PubChem CID 1011240, C22H24Cl2N2O4, 451.3 g/mol, IUPAC name 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The synonyms list CAS 1597403-47-8, 548470-11-7 and 1597403-48-9, and the names trans-ISRIB, ISRIB (trans-isomer) and a cis-cyclohexane name; which number belongs to which isomer was not resolved. A 2016 structure-activity paper calls the class bis-O-arylglycolamides (PMID 26789650). The clinical-stage molecules that get grouped with ISRIB are separate compounds: DNL343 (Denali), fosigotifator (ABBV-CLS-7262, AbbVie), and ISRIB-like compounds such as 2BAct and PRXS571. A 2026 medicinal chemistry paper says fosigotifator came from replacing the cyclohexyl core and side chains of ISRIB, through a truncated analogue (2BAct) and a prodrug step, so it is a descendant and not ISRIB. Nothing in the clinical record on this page was run with ISRIB.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, free form
Follow-up
Not applicable
Study design
Chemical database record; original chemistry papers
Funding
not stated in the source

Identity record only. The stereochemistry of any vendor material should be confirmed, and no public record ties any vendor material to the studied compound.

Read the original source

Why does ISRIB sit in C tier?

ISRIB has an unusually well-established mechanism, consistent rodent memory results from more than one laboratory and no documented harm from ISRIB itself in people, but it has never been tested in a registered or published human study, its poor solubility limits absorption, and trials of two analogs found no slowing in ALS.

The mechanism is unusually well established (structure, allostery at eIF2B, many laboratories), the rodent memory results after injury and in aging are consistent across more than one laboratory, and nothing in the records reviewed documents harm from ISRIB itself in people.

Against that, ISRIB has never been tested in a registered or published human study, a 2026 paper says poor solubility limits its absorption, a worsened-outcome result exists for ISRIB-like activators in an ALS mouse model, and the two clinical trials of analog drugs found no slowing in ALS. C is assigned at the thin end.

2013 discovery from a PERK cell screen (IC50 5 nM), better learning in mice, and the 2021 eIF2B binding structures

Animal study

Sidrauski C et al. Elife. 2013;2:e00498. PMID 23741617.

A cell-based screen for inhibitors of PERK signaling found ISRIB, which reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and ISRIB-treated mice showed significant enhancement of spatial and fear-associated learning; dose and route are not in the abstract. The 2013 abstract also reports that ISRIB reduces the viability of cells subjected to PERK activation by chronic ER stress. A 2021 paper shows ISRIB binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, with cryo-EM structures, so the mechanism is well defined in vitro (PMID 33220178).

Participants / model
Cell lines; mice
Treatment
Cell assays; the in vivo route is not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical studies
Funding
not stated in the source

Discovery paper plus a paper on the eIF2B binding structures. Neither gives an in vivo dose or route in its abstract.

Read the original source
Brain injury, head injury, postoperative and vascular models; one chronic stress study

Animal study

Chou A et al. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. PMID 28696288.

In two mouse models of traumatic brain injury (focal contusion and diffuse concussive injury), ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped; long-term potentiation, suppressed by injury, was fully restored. In mice with mild repetitive head injury, which increased risk-taking behavior in males but not females, ISRIB given weeks later reversed the behavior and restored cell-specific synaptic function (PMID 31884883). In adult rats exposed to ethanol in adolescence, ISRIB improved spatial learning and memory impairment and neuronal damage (PMID 39142353), and in a rat model of vascular cognitive impairment (permanent bilateral carotid occlusion), ISRIB microinjected into the hippocampal dentate gyrus improved spatial, working and recognition memory and restored synaptic markers (PMID 41380823), which is local brain delivery and not a systemic route. In mice with a tibial fracture under isoflurane, a model of postoperative cognitive dysfunction, ISRIB lowered ISR and oxidative stress markers in the hippocampus and ameliorated cognitive dysfunction (PMID 36212697). In one mouse study of chronic restraint stress, 2 weeks of ISRIB improved depression-like behavior and reversed hypothalamic-pituitary-adrenal axis hyperactivity in male mice, and in females improved anhedonia but not forced-swim or tail-suspension immobility (PMID 38942086).

Participants / model
Mice with traumatic brain injury; mice with repetitive head injury; mice with postoperative cognitive dysfunction or chronic restraint stress; rats
Treatment
ISRIB; not stated in most abstracts, microinjection into the dentate gyrus in the rat vascular study
Follow-up
Treatment given weeks after injury in the mouse injury studies; 2 weeks in the restraint stress study
Study design
Original preclinical studies
Funding
not stated in the source

Results come from several laboratories, all in rodents. The chronic restraint stress result measures mood-like behavior with a sex difference, not memory, and is not used for the memory claim. Doses and routes are not in most abstracts.

Read the original source
PubMed, 10 October 2026: 258 records, none with a clinical publication type

PubMed search record

PubMed search run 10 October 2026: ISRIB[tiab], with follow-up queries adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study or phase I or II clinical trial, and a broader human-terms query.

A PubMed query run on 10 October 2026 for ISRIB[tiab] returned 258 records, and adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study, or phase I or II clinical trial returned 0 records. A broader human-terms query returned 163 records, and the 40 top-ranked titles were screened and were cell, animal, protein-structure or review papers; the one human-patient report is the ALSUntangled assessment of self-reported use, which could not be confirmed. The 2025 safety review says news of clinical trials has circulated without published information (PMID 38757325), and no registered ISRIB trial was found. ISRIB is a research compound with human use limited to self-reported anecdote in the records reviewed, and the human evidence in this field comes from analogs.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated literature search
Funding
not stated in the source

An absence finding as of 10 October 2026, not proof that no unpublished or unindexed work exists. Only the 40 top-ranked titles of the broader query were screened.

Read the original source
Different drug: DNL343 in 249 people with ALS, rate ratio 1.04, no slowing

Randomized controlled trial

Paganoni S et al. JAMA Netw Open. 2026;9(9):e2634809. PMID 42771346.

Denali's eIF2B activator DNL343 was tested in Phase 1 and Phase 1b randomized trials in healthy and ALS participants (NCT04268784 and NCT05006352 per the paper), where it showed extensive CSF distribution, was generally well tolerated, and reduced ISR biomarkers in blood cells and CSF (PMID 40825784). In the HEALEY ALS Platform Trial regimen (NCT05842941, 74 US centers, 24 weeks, 200 mg per day), 249 participants were randomized to DNL343 (n = 186) or regimen-specific placebo (n = 63), analyzed with 139 shared placebo participants; the median disease rate ratio was 1.04 (95% credible interval 0.83 to 1.32, probability of rate ratio below 1 of 0.37), secondary measures did not differ, adverse event rates were similar, and the authors conclude 200 mg per day did not show evidence of slowing ALS progression. A 2025 paper states DNL343 is an investigational drug not approved by any health authority.

Participants / model
People with ALS; healthy participants
Treatment
Oral DNL343, a different molecule from ISRIB
Follow-up
24 weeks in the HEALEY ALS Platform Trial regimen
Study design
Randomized clinical trial and early-phase trial report, of an ISRIB-like drug in motor neuron disease
Funding
not stated in the source

This is a different molecule in a motor neuron disease, and it says nothing about memory or about ISRIB itself.

Read the original source
Different drug: fosigotifator in 310 people with ALS, posted rate ratios near 1, no peer-reviewed report found

Trial registry record

ClinicalTrials.gov. NCT05740813. HEALEY ALS Platform Trial regimen of fosigotifator (ABBV-CLS-7262), Phase 2 and 3, 310 participants enrolled, with other fosigotifator records NCT05757141, NCT06618118 and NCT04948645.

NCT05740813 is a HEALEY ALS regimen (Phase 2 and 3, 310 participants enrolled, start 2023-03-23, primary completion 2024-10-03, two oral doses against placebo for 24 weeks, results posted on the registry). The two posted primary-outcome analyses give disease rate ratios of 1.06 (confidence interval 0.850 to 1.324) and 0.96 (0.753 to 1.220), which does not show slowing. No peer-reviewed report was found in PubMed; a query on the drug names returned the chemistry paper only. Other records are an open-label exploratory study in vanishing white matter disease (NCT05757141, 50 participants estimated, recruiting), a Phase 1b in major depressive disorder (NCT06618118, 20 enrolled, terminated, no results posted), an ALS Phase 1 (NCT04948645, 31 enrolled, terminated), and several healthy-volunteer pharmacology studies.

Participants / model
People with ALS; people with vanishing white matter disease or major depressive disorder; healthy volunteers
Treatment
Oral fosigotifator, a prodrug-derived analog and not ISRIB
Follow-up
24 weeks in the HEALEY ALS regimen; start 2023-03-23, primary completion 2024-10-03
Study design
Registry records of Phase 1, Phase 1b, exploratory and Phase 2 and 3 studies
Funding
not stated in the source

The posted figures are registry entries and the full results tables were not read. The drug is a prodrug-derived analog, not ISRIB. The results should be compared with a peer-reviewed report when one appears.

Read the original source

Studies and sources

PubChem: ISRIB identity, isomers and CAS numbers, and what ISRIB is not

Chemical identity record

PubChem, National Library of Medicine. Compound summary for CID 1011240, 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide (ISRIB).

ISRIB (integrated stress response inhibitor) is PubChem CID 1011240, C22H24Cl2N2O4, 451.3 g/mol, IUPAC name 2-(4-chlorophenoxy)-N-[4-[[2-(4-chlorophenoxy)acetyl]amino]cyclohexyl]acetamide. The synonyms list CAS 1597403-47-8, 548470-11-7 and 1597403-48-9, and the names trans-ISRIB, ISRIB (trans-isomer) and a cis-cyclohexane name; which number belongs to which isomer was not resolved. A 2016 structure-activity paper calls the class bis-O-arylglycolamides (PMID 26789650). The clinical-stage molecules that get grouped with ISRIB are separate compounds: DNL343 (Denali), fosigotifator (ABBV-CLS-7262, AbbVie), and ISRIB-like compounds such as 2BAct and PRXS571. A 2026 medicinal chemistry paper says fosigotifator came from replacing the cyclohexyl core and side chains of ISRIB, through a truncated analogue (2BAct) and a prodrug step, so it is a descendant and not ISRIB. Nothing in the clinical record on this page was run with ISRIB.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, free form
Follow-up
Not applicable
Study design
Chemical database record; original chemistry papers
Funding
not stated in the source

Identity record only. The stereochemistry of any vendor material should be confirmed, and no public record ties any vendor material to the studied compound.

Read the original source
2013 discovery from a PERK cell screen (IC50 5 nM), better learning in mice, and the 2021 eIF2B binding structures

Animal study

Sidrauski C et al. Elife. 2013;2:e00498. PMID 23741617.

A cell-based screen for inhibitors of PERK signaling found ISRIB, which reverses the effects of eIF2 alpha phosphorylation with an IC50 of 5 nM, and ISRIB-treated mice showed significant enhancement of spatial and fear-associated learning; dose and route are not in the abstract. The 2013 abstract also reports that ISRIB reduces the viability of cells subjected to PERK activation by chronic ER stress. A 2021 paper shows ISRIB binds eIF2B and antagonizes the inhibitory effect of phosphorylated eIF2 allosterically, with cryo-EM structures, so the mechanism is well defined in vitro (PMID 33220178).

Participants / model
Cell lines; mice
Treatment
Cell assays; the in vivo route is not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical studies
Funding
not stated in the source

Discovery paper plus a paper on the eIF2B binding structures. Neither gives an in vivo dose or route in its abstract.

Read the original source
Old mice: spatial and working memory, spine density, hippocampal physiology

Animal study

Krukowski K et al. Elife. 2020;9. PMID 33258451.

ISRIB reversed ISR activation in the brain of old mice (lower ATF4 and phosphorylated eIF2), reversed spatial memory deficits, ameliorated working memory, rescued intrinsic neuronal electrophysiology, restored spine density, and reduced interferon and T cell immune profiles in the hippocampus. The abstract gives no dose, route or schedule.

Participants / model
Old mice
Treatment
ISRIB; dose, route and schedule not stated in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

Krukowski K, Rosi S and Walter P are authors here and on the injury papers, where the conflict statements say Walter P holds a patent on ISRIB licensed to Calico; this record shows no conflict statement.

Read the original source
Brain injury, head injury, postoperative and vascular models; one chronic stress study

Animal study

Chou A et al. Proc Natl Acad Sci U S A. 2017;114(31):E6420-E6426. PMID 28696288.

In two mouse models of traumatic brain injury (focal contusion and diffuse concussive injury), ISRIB reversed hippocampal-dependent cognitive deficits, including when given weeks after the injury, and the memory gain persisted after treatment stopped; long-term potentiation, suppressed by injury, was fully restored. In mice with mild repetitive head injury, which increased risk-taking behavior in males but not females, ISRIB given weeks later reversed the behavior and restored cell-specific synaptic function (PMID 31884883). In adult rats exposed to ethanol in adolescence, ISRIB improved spatial learning and memory impairment and neuronal damage (PMID 39142353), and in a rat model of vascular cognitive impairment (permanent bilateral carotid occlusion), ISRIB microinjected into the hippocampal dentate gyrus improved spatial, working and recognition memory and restored synaptic markers (PMID 41380823), which is local brain delivery and not a systemic route. In mice with a tibial fracture under isoflurane, a model of postoperative cognitive dysfunction, ISRIB lowered ISR and oxidative stress markers in the hippocampus and ameliorated cognitive dysfunction (PMID 36212697). In one mouse study of chronic restraint stress, 2 weeks of ISRIB improved depression-like behavior and reversed hypothalamic-pituitary-adrenal axis hyperactivity in male mice, and in females improved anhedonia but not forced-swim or tail-suspension immobility (PMID 38942086).

Participants / model
Mice with traumatic brain injury; mice with repetitive head injury; mice with postoperative cognitive dysfunction or chronic restraint stress; rats
Treatment
ISRIB; not stated in most abstracts, microinjection into the dentate gyrus in the rat vascular study
Follow-up
Treatment given weeks after injury in the mouse injury studies; 2 weeks in the restraint stress study
Study design
Original preclinical studies
Funding
not stated in the source

Results come from several laboratories, all in rodents. The chronic restraint stress result measures mood-like behavior with a sex difference, not memory, and is not used for the memory claim. Doses and routes are not in most abstracts.

Read the original source
Prion mice without pancreatic toxicity; proteasome impairment in cells; analogs worsened ALS mice

Animal study

Marlin E et al. Br J Pharmacol. 2024;181(3):495-508. PMID 37823684.

In prion-diseased mice ISRIB gave neuroprotection with no adverse effect on the pancreas, and only partial restoration of global translation, which the authors say spares protective stress responses in secretory tissue, in contrast to the PERK inhibitor GSK2606414 that was toxic to the pancreas (PMID 25741597). In cell experiments ISRIB impaired degradation of proteins by the cytosolic ubiquitin-proteasome system during proteotoxic stress, with accumulation comparable to a proteasome inhibitor, and the authors flag a risk that ISR inhibition compromises recovery of protein homeostasis (PMID 39379572). The two ISRIB-like eIF2B activators 2BAct and PRXS571 anticipated disease onset, aggravated muscle denervation and motor neuron death, and shortened survival in SOD1 G93A ALS mice, which the authors say reveals toxicity eIF2B activators may display in ALS patients. A 2025 narrative review says ISRIB's long-term safety is open and that rumors suggest efficacy versus safety may be compromised by side effects (PMID 38757325).

Participants / model
Prion-infected mice; cell lines; SOD1 G93A mice; review
Treatment
Not stated in the abstracts
Follow-up
not stated in the source
Study design
Original preclinical studies; review abstract
Funding
not stated in the source

The ALS mouse results are for the analogs and for ALS mice and do not show that ISRIB itself is harmful in people; they show the pathway has a protective role under some stresses.

Read the original source
ISRIB solubility, self-reported use and a topical cream; no ISRIB trials in any condition

Case report

Mascias Cadavid J et al. Amyotroph Lateral Scler Frontotemporal Degener. 2025;26(7-8):821-824. PMID 40762148.

The 2026 fosigotifator paper states that ISRIB's poor solubility limits absorption and advancement, and that the truncated analogue 2BAct had better solubility but cardiovascular effects in higher species limited its progress (PMID 42153306). The ALSUntangled assessment (2025) says questions about ISRIB's solubility and bioavailability have arisen, that a small number of patients taking ISRIB in Spain report symptomatic improvements with little or no side effects that the reviewers could not confirm independently, and that there are no clinical trials evaluating ISRIB in any condition; it concludes there is not enough evidence to endorse its use for ALS. A 2024 formulation paper builds a topical cream of ISRIB for chemical-injury skin damage and reports delivery into skin with no detectable systemic exposure (PMID 39244069). No ISRIB pharmacokinetic figure (half-life, bioavailability or brain level) appears in the abstracts read.

Participants / model
Human patients (self-reports); formulation experiments
Treatment
Oral self-use reports; topical cream
Follow-up
not stated in the source
Study design
Expert assessment of self-reported use and the literature (ALSUntangled), a medicinal chemistry paper and a formulation paper; not a clinical study
Funding
not stated in the source

Anecdote that the reviewers could not confirm, not a study. It is the only report of human use of ISRIB itself in the records reviewed.

Read the original source
Different drug: DNL343 in 249 people with ALS, rate ratio 1.04, no slowing

Randomized controlled trial

Paganoni S et al. JAMA Netw Open. 2026;9(9):e2634809. PMID 42771346.

Denali's eIF2B activator DNL343 was tested in Phase 1 and Phase 1b randomized trials in healthy and ALS participants (NCT04268784 and NCT05006352 per the paper), where it showed extensive CSF distribution, was generally well tolerated, and reduced ISR biomarkers in blood cells and CSF (PMID 40825784). In the HEALEY ALS Platform Trial regimen (NCT05842941, 74 US centers, 24 weeks, 200 mg per day), 249 participants were randomized to DNL343 (n = 186) or regimen-specific placebo (n = 63), analyzed with 139 shared placebo participants; the median disease rate ratio was 1.04 (95% credible interval 0.83 to 1.32, probability of rate ratio below 1 of 0.37), secondary measures did not differ, adverse event rates were similar, and the authors conclude 200 mg per day did not show evidence of slowing ALS progression. A 2025 paper states DNL343 is an investigational drug not approved by any health authority.

Participants / model
People with ALS; healthy participants
Treatment
Oral DNL343, a different molecule from ISRIB
Follow-up
24 weeks in the HEALEY ALS Platform Trial regimen
Study design
Randomized clinical trial and early-phase trial report, of an ISRIB-like drug in motor neuron disease
Funding
not stated in the source

This is a different molecule in a motor neuron disease, and it says nothing about memory or about ISRIB itself.

Read the original source
Different drug: fosigotifator in 310 people with ALS, posted rate ratios near 1, no peer-reviewed report found

Trial registry record

ClinicalTrials.gov. NCT05740813. HEALEY ALS Platform Trial regimen of fosigotifator (ABBV-CLS-7262), Phase 2 and 3, 310 participants enrolled, with other fosigotifator records NCT05757141, NCT06618118 and NCT04948645.

NCT05740813 is a HEALEY ALS regimen (Phase 2 and 3, 310 participants enrolled, start 2023-03-23, primary completion 2024-10-03, two oral doses against placebo for 24 weeks, results posted on the registry). The two posted primary-outcome analyses give disease rate ratios of 1.06 (confidence interval 0.850 to 1.324) and 0.96 (0.753 to 1.220), which does not show slowing. No peer-reviewed report was found in PubMed; a query on the drug names returned the chemistry paper only. Other records are an open-label exploratory study in vanishing white matter disease (NCT05757141, 50 participants estimated, recruiting), a Phase 1b in major depressive disorder (NCT06618118, 20 enrolled, terminated, no results posted), an ALS Phase 1 (NCT04948645, 31 enrolled, terminated), and several healthy-volunteer pharmacology studies.

Participants / model
People with ALS; people with vanishing white matter disease or major depressive disorder; healthy volunteers
Treatment
Oral fosigotifator, a prodrug-derived analog and not ISRIB
Follow-up
24 weeks in the HEALEY ALS regimen; start 2023-03-23, primary completion 2024-10-03
Study design
Registry records of Phase 1, Phase 1b, exploratory and Phase 2 and 3 studies
Funding
not stated in the source

The posted figures are registry entries and the full results tables were not read. The drug is a prodrug-derived analog, not ISRIB. The results should be compared with a peer-reviewed report when one appears.

Read the original source
PubMed, 10 October 2026: 258 records, none with a clinical publication type

PubMed search record

PubMed search run 10 October 2026: ISRIB[tiab], with follow-up queries adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study or phase I or II clinical trial, and a broader human-terms query.

A PubMed query run on 10 October 2026 for ISRIB[tiab] returned 258 records, and adding the publication types clinical trial, randomized controlled trial, case reports, clinical study, observational study, or phase I or II clinical trial returned 0 records. A broader human-terms query returned 163 records, and the 40 top-ranked titles were screened and were cell, animal, protein-structure or review papers; the one human-patient report is the ALSUntangled assessment of self-reported use, which could not be confirmed. The 2025 safety review says news of clinical trials has circulated without published information (PMID 38757325), and no registered ISRIB trial was found. ISRIB is a research compound with human use limited to self-reported anecdote in the records reviewed, and the human evidence in this field comes from analogs.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated literature search
Funding
not stated in the source

An absence finding as of 10 October 2026, not proof that no unpublished or unindexed work exists. Only the 40 top-ranked titles of the broader query were screened.

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Label and registry searches, 10 October 2026: no label, no ISRIB study

Regulatory record

U.S. Food and Drug Administration (DailyMed label search) and ClinicalTrials.gov. Searches for ISRIB, integrated stress response inhibitor and eIF2B activator, run 10 October 2026.

A ClinicalTrials.gov query for ISRIB run on 10 October 2026 returned no studies, nor did queries for 'integrated stress response' inhibitor and 'eIF2B activator'. DailyMed returned no label for ISRIB. No registered ISRIB trial was found.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 10 October 2026
Study design
Dated label and registry search
Funding
not stated in the source

An absence finding as of 10 October 2026. It covers United States label and registry records only.

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Why is ISRIB in C tier?

C, at the thin end, fits a research compound with an unusually well-established mechanism and consistent rodent memory results from more than one laboratory, with no documented harm from ISRIB itself in people. It has never been tested in a registered or published human study, its poor solubility limits absorption, an ISRIB-like activator worsened an ALS mouse model, and trials of two clinical-stage analogs found no slowing in ALS.