Dihexa

Overview

Dihexa (PNB-0408) is a small-molecule, hexapeptide-like analog of angiotensin IV developed at Washington State University as a preclinical candidate for Alzheimer's disease and cognitive decline. It is not FDA-approved and has never been tested in humans. The frequently-quoted 'ten million times more potent than BDNF' figure refers to an in-vitro dendritic-spine EC50 comparison, not clinical potency.

Mechanism of Action

Dihexa binds with high affinity to hepatocyte growth factor (HGF) and facilitates HGF/c-Met receptor dimerization at otherwise subthreshold HGF concentrations, downstream of which it promotes dendritic spine formation and hippocampal synaptogenesis. It does not appear to act through classical angiotensin receptors despite being derived from angiotensin IV, and was designed for oral bioavailability and blood-brain-barrier penetration.

Research Summary

McCoy et al. (J Pharmacol Exp Ther 2013, PMID 23055539) is the original dihexa characterization: oral dihexa reversed scopolamine-induced memory deficits and improved Morris water maze performance in aged rats at low doses. Sun et al. (Brain Sci 2021, PMID 34827486) reported that dihexa rescued cognitive impairment in the APP/PS1 Alzheimer's mouse via PI3K/AKT signaling, with increased synaptophysin and reduced neuroinflammation. Wright & Harding (J Alzheimers Dis 2015, PMID 25649658) reviewed the brain HGF/c-Met system as an Alzheimer's target. Note: Benoist et al. (JPET 2014, PMID 25187433), which reported the HGF/c-Met-dependent synaptogenesis mechanism, was retracted in 2025 and should not be relied on as primary evidence. The 'roughly seven orders of magnitude more potent than BDNF' descriptor refers to in vitro dendritic spine EC50 values, not clinical efficacy. Dihexa has never entered human clinical trials; Athira Pharma's related analog fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's endpoint in 2024 and was discontinued, after which Athira shifted focus to ATH-1105 for ALS.

Prescribers who offer Dihexa

32 prescribers in our directory work with Dihexa, each confirmed from their own website. Peptides like Dihexa require a prescription from a licensed provider.

Reported Side Effects

• No human safety data — all listed effects are theoretical or anecdotal
• Headache and overstimulation reported anecdotally by self-experimenters
• Theoretical blood pressure effects from the angiotensin-derived scaffold (not clinically demonstrated)
• Completely unknown long-term effects

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Compare Dihexa with Others

Research References

• McCoy AT, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141-154.
• Sun X, et al. Dihexa rescues cognitive impairment in the APP/PS1 Alzheimer's mouse model. Brain Sci. 2021.

Frequently asked questions

Has Dihexa been independently lab-tested?

Disclosed Labs has collected 4 Certificates of Analysis (COA) for Dihexa from 4 independent testing labs. 4 vendors have submitted material for testing. Products average 99.1% tested purity across the corpus. Full testing data is available at https://www.disclosedlabs.com/peptides/dihexa/testing.

What is the average purity of Dihexa on the market?

Based on 4 COAs analyzed by Disclosed Labs, Dihexa products average 99.1% (±0.9%) tested purity. Individual vendor results vary; see per-vendor COA data at https://www.disclosedlabs.com/peptides/dihexa/coas.

Which prescribers offer Dihexa with a prescription?

32 prescribers in the Disclosed Labs directory work with Dihexa, each confirmed from their own website. Dihexa requires a prescription from a licensed provider. Browse them at https://www.disclosedlabs.com/prescribers?peptide=Dihexa.

How does Dihexa work?

Dihexa binds with high affinity to hepatocyte growth factor (HGF) and facilitates HGF/c-Met receptor dimerization at otherwise subthreshold HGF concentrations, downstream of which it promotes dendritic spine formation and hippocampal synaptogenesis. It does not appear to act through classical angiotensin receptors despite being derived from angiotensin IV, and was designed for oral bioavailability and blood-brain-barrier penetration.

What does the research say about Dihexa?

McCoy et al. (J Pharmacol Exp Ther 2013, PMID 23055539) is the original dihexa characterization: oral dihexa reversed scopolamine-induced memory deficits and improved Morris water maze performance in aged rats at low doses. Sun et al. (Brain Sci 2021, PMID 34827486) reported that dihexa rescued cognitive impairment in the APP/PS1 Alzheimer's mouse via PI3K/AKT signaling, with increased synaptophysin and reduced neuroinflammation. Wright & Harding (J Alzheimers Dis 2015, PMID 25649658) reviewed the brain HGF/c-Met system as an Alzheimer's target. Note: Benoist et al. (JPET 2014, PMID 25187433), which reported the HGF/c-Met-dependent synaptogenesis mechanism, was retracted in 2025 and should not be relied on as primary evidence. The 'roughly seven orders of magnitude more potent than BDNF' descriptor refers to in vitro dendritic spine EC50 values, not clinical efficacy. Dihexa has never entered human clinical trials; Athira Pharma's related analog fosgonimeton failed its Phase 2/3 LIFT-AD Alzheimer's endpoint in 2024 and was discontinued, after which Athira shifted focus to ATH-1105 for ALS.