Dihexa and Cognitive Enhancement: What Has Been Studied

What the research covers

Dihexa has not been tested in humans. A PubMed search found 18 dihexa records, and none gave it to people. Dihexa is a man-made compound based on angiotensin IV. It was designed as a possible drug for dementia, such as Alzheimer's disease.

A 2013 study tested it in rodents (rat) with memory loss from old age or a drug. The authors reported anti-dementia effects in both models. In 2021, the journal put a notice of concern on that paper. A 2014 paper by the same group said dihexa works through a growth factor called HGF. The journal has since retracted that paper.

A later study used rodents (mouse) bred as a model of Alzheimer's disease. Dihexa restored their learning in a water maze. It also lowered two inflammation signals, IL-1 beta and TNF-alpha.

The ClinicalTrials.gov registry listed no dihexa trials either. So nothing is known about its dose, effects or safety in people.

Sources

1. McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther (2013). PMID 23055539 doi:10.1124/jpet.112.199497 Rodent (rat): dihexa developed as a procognitive/antidementia agent; scopolamine and aged models. Under an expression of concern since 2021.
2. Notice of Concern: McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, and Harding JW (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents, J Pharmacol Exp Ther, 344: 141-154; DOI: https://doi.org/10.1124/jpet.112.199497. J Pharmacol Exp Ther (2021). PMID 34551989 doi:10.1124/jpet.112.199497concern The journal's 2021 notice of concern on the 2013 dihexa paper.
3. Benoist CC, Kawas LH, Zhu M, et al. Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" [J Pharmacol Exp Ther 351 (2014) 390-402]. J Pharmacol Exp Ther (2025). PMID 40312093 doi:10.1016/j.jpet.2025.103567 The journal's 2025 retraction of the 2014 paper that proposed dihexa acts via HGF/c-Met.
4. Sun X, Deng Y, Fu X, et al. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci (2021). PMID 34827486 doi:10.3390/brainsci11111487 Rodent (mouse) APP/PS1 Alzheimer's model: dihexa restored water maze performance and lowered IL-1 beta and TNF-alpha.