Dihexa

Also known as: PNB-0408

Evidence: Preclinical

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Overview

Angiotensin IV-derived peptide analog; rodent studies report memory rescue in some models, but the founding papers for its HGF/c-Met mechanism were retracted in 2025.

Dihexa is a small modified peptide derived from angiotensin IV, developed as a procognitive agent. Two of the developer group's foundational papers, which proposed HGF/c-Met activation and synaptogenesis, were retracted in April 2025, and a third (McCoy 2013) has carried an expression of concern since 2021. Independent rodent studies are mixed: memory rescue in APP/PS1 mice and after repeated mild brain injury, no protection in a rat Huntington-like model. There are no human trials. Its clinical successor, fosgonimeton, failed a phase 2/3 Alzheimer's trial.

Benefits

Memory rescue in some rodent models (mixed results; one rat model showed no protection)

Dosing reference

Research dose: 10-30 mcg daily (oral) - no established human dose
Range: 10 to 30 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 10 mg, 20 mg

No published human dose. Earlier potency claims trace to papers retracted in 2025.

Mechanism

Proposed. The HGF/c-Met mechanism and the claim of potency about 10 million times that of BDNF come from papers retracted in April 2025 (notices PMID 40312092 and 40312093) and are not treated as established. McCoy et al., 2013 described dihexa as a metabolically stabilized angiotensin IV analog; that paper has an expression of concern. Independent work reported memory rescue in APP/PS1 mice with PI3K/AKT pathway changes (Sun et al., 2021) and rescue of working memory after repeated mild traumatic brain injury in rodents (Martino et al., 2025).

Evidence

Preclinical: animal or in vitro data only

Metabolically stabilized angiotensin IV analogs including dihexa were procognitive in rodent dementia models (McCoy et al., 2013); the paper has carried an expression of concern since 2021
Dihexa rescued cognitive impairment in APP/PS1 mice, with PI3K/AKT signalling changes (Sun et al., 2021)
Dihexa did not protect against 3-nitropropionic acid-induced Huntington-like symptoms in rats (Wells et al., 2024)
An HGF/MET activator rescued working memory deficits after repeated mild traumatic brain injury in rodents (Martino et al., 2025)
Two foundational papers from the developer group were retracted in April 2025 (notices PMID 40312092 and 40312093)
Human-trial status: none for dihexa. Its successor compound fosgonimeton failed the LIFT-AD phase 2/3 trial in mild-to-moderate Alzheimer's disease, NCT04488419 (Porsteinsson et al., 2025)

References

Side effects

No human safety data. The proposed mechanism is HGF/c-Met activation, a pathway linked to tumor growth, so a theoretical concern about existing tumors has been raised; the papers that established that mechanism are retracted. Commonly reported (anecdotal): headache, irritability.

Storage

Storage: Room temperature, away from light
Lyophilized: 12+ months
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not established in humans; no half-life verified from non-retracted sources
Bioavailability: Not measured in humans. Oral and subcutaneous activity claims come from the original developer group, whose foundational papers were retracted
Molecular weight: 504.7 Da
Sequence: N-hexanoyl-Tyr-Ile-(6)-aminohexanoic amide (modified dipeptide)