Dihexa
Dihexa (N-hexanoic-Tyr-Ile-(6)aminohexanoic amide, also designated PNB-0408) is a synthetic oligopeptide derivative of angiotensin IV, originally developed at Washington State University by researchers investigating the renin-angiotensin system's role in cognitive function. It has attracted intense interest in nootropic and neuroscience communities due to early research suggesting it promotes synaptogenesis, the formation of new synaptic connections between neurons, through a unique mechanism involving hepatocyte growth factor (HGF) and its receptor c-Met.
Dihexa works by binding to and allosterically activating hepatocyte growth factor, creating an active HGF-Dihexa heterodimer that enhances c-Met receptor phosphorylation and downstream signaling at concentrations where HGF alone would be insufficient. This mechanism promotes dendritic spine formation and synaptic connectivity, which are fundamental processes in learning and memory. Animal studies have demonstrated that Dihexa can restore spatial learning and cognitive function in models of chemically induced amnesia, with improvements in both short- and long-term memory. A 2021 independent study (Chai et al.)[1] confirmed cognitive improvements in APP/PS1 Alzheimer's model mice via the PI3K/AKT signaling pathway.
Important caveats surround Dihexa research. The foundational 2014 paper establishing the HGF/c-Met mechanism (Benoist et al.)[2] was formally retracted in April 2025 due to image manipulation concerns, though the independent 2021 Chinese study remains in good standing. No human clinical trials have been conducted, and no studies have evaluated long-term safety, including potential tumorigenic and cancer-metastatic effects. This is a significant concern given that HGF/c-Met signaling is implicated in cancer progression. Dihexa crosses the blood-brain barrier and can be administered orally, but it should be regarded as an early-stage experimental compound with substantial unanswered safety questions.
Key Details
| Category | Nootropic/Cognitive |
| Primary Uses | Cognitive enhancement research, Synaptogenesis and neuroplasticity studies, Alzheimer's disease research, Memory and learning research, Neurodegenerative disease investigation |
| Mechanism of Action | Allosteric activator of hepatocyte growth factor (HGF); forms HGF-Dihexa heterodimer that enhances c-Met receptor phosphorylation; promotes dendritic spine formation and synaptogenesis; crosses blood-brain barrier |
| Administration Route | Oral, Subcutaneous injection, Intranasal (research) |
| Typical Research Dosage | 5-20mg orally or 0.5-2mg subcutaneously (research protocols; no established human dosing) |
| Protocol Duration | Variable in research; no established protocol duration |
| Half-Life | Not well-characterized in humans |
| Legal Status | Not FDA-approved; available as research chemical; no regulatory classification |
| FDA Status | Not approved by the FDA. No human clinical trials registered or completed. Purely preclinical research compound. |
| Notable Studies | Animal studies: Restored spatial learning and cognitive function in Morris water maze after chemically induced amnesia, 2021 independent study (Chai et al.): Confirmed cognitive improvement in APP/PS1 Alzheimer's mice via PI3K/AKT pathway, IMPORTANT: 2014 foundational paper (Benoist et al.) retracted in April 2025 due to image manipulation concerns, Demonstrated enhancement of long-term potentiation (LTP), the neurophysiological basis of memory storage, Shown to promote dendritic spine formation and synaptic connectivity in preclinical models |
| Safety Profile | Significant safety unknowns. No human studies conducted. No long-term safety evaluations performed. Major theoretical concern: HGF/c-Met pathway activation is implicated in cancer progression and metastasis. Tumorigenic potential has not been studied. Should be regarded as an early experimental compound with substantial unanswered safety questions. |
| Typical Price Range | $45-80 per 10mg vial |
| Molecular Weight | 507.63 Da |
References
- Dihexa Improves Cognitive Function in APP/PS1 Mice via PI3K/AKT Pathway (2021)
- Retracted: N-Hexanoic-Tyr-Ile-(6) Aminohexanoic Amide (Dihexa) and Hepatocyte Growth Factor (2014)
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