Dihexa
NootropicPNB-0408 — Synthetic Peptide
Overview
Dihexa (developmental code PNB-0408) is a synthetic oligopeptide derived from angiotensin IV (Ang IV), a component of the brain renin-angiotensin system. It was developed at Washington State University as an orally bioavailable, blood-brain barrier-permeable cognitive enhancer. Dihexa is a modified hexapeptide designed to bind hepatocyte growth factor (HGF) and potentiate its signaling through the c-Met receptor, a mechanism initially proposed as a potent promoter of hippocampal synaptogenesis and cognitive enhancement.
**Critical research integrity concern:** The principal mechanistic paper underpinning Dihexa's mechanism of action (Benoist et al., 2014) was formally retracted in April 2025 following a Washington State University investigation finding that co-author Leen Kawas falsified western blot data. Kawas later founded Athira Pharma, which developed a Dihexa prodrug (fosgonimeton/ATH-1017) for Alzheimer's disease; the company settled False Claims Act allegations for $4 million in 2025 related to NIH grants referencing the compromised research.
Despite this, some independent animal research (Sun et al., 2021) not implicated in the retraction demonstrates cognitive benefits via PI3K/AKT signaling in Alzheimer's mouse models. No human clinical trials of Dihexa have been published. Fosgonimeton (the prodrug) entered Phase 2 trials under Athira Pharma before the company's restructuring.
Mechanism of Action
As originally proposed, Dihexa bound with high affinity to HGF and potentiated its activity at the c-Met receptor in the hippocampus. This HGF/c-Met engagement was claimed to drive dendritic spine formation (spinogenesis) and new synapse development (synaptogenesis), mechanistically mimicking the effects of exogenous HGF on neural connectivity. This mechanism was described as approximately 10 million-fold more potent than BDNF in inducing synaptic growth — a claim that, given the retraction of the underlying data, must now be treated as unvalidated.
The independent Sun et al. study identified PI3K/AKT signaling as an alternative pathway through which Dihexa-related compounds may rescue cognitive impairment, and angiotensin IV's known interaction with the AT4 receptor (IRAP) provides additional mechanistic context that remains uncontested. The peptide is orally bioavailable and crosses the blood-brain barrier — structural properties that are not in dispute.
Research Dosing
No human dose has been established or tested in published clinical trials. Dihexa is orally bioavailable and BBB-permeable in animal studies. Human dosing used in nootropic communities is entirely anecdotal with no safety validation.
Subcutaneous administration has been explored in preclinical models. No human data.
Research data only. These dosing ranges are derived from published studies, primarily in animal models. This is not medical advice. No peptide discussed on this site is approved for human therapeutic use unless otherwise noted.
Published Studies
The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system
Benoist CC, Kawas LH, Zhu M, et al. — Journal of Pharmacology and Experimental Therapeutics, 2014
Demonstrated that Dihexa potentiates HGF activity at the c-Met receptor, inducing hippocampal spinogenesis and synaptogenesis in mice with cognitive benefits blocked by HGF antagonists. NOTE: This article was formally retracted in April 2025 following a university investigation confirming falsified figures attributed to co-author Leen Kawas. The behavioral data was not directly implicated but the mechanistic foundation is now compromised.
PMID: 25187433 →AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway
Sun J, Zhang S, Zhang X, Zhang Y, Dong H, Qian Y — Brain Sciences, 2021
Independent study (not implicated in the retraction) demonstrating that Dihexa rescued cognitive impairment and memory deficits in an Alzheimer's mouse model (APP/PS1) via PI3K/AKT pathway activation, providing some independent mechanistic support separate from the retracted HGF/c-Met work.