Dihexa is a synthetic angiotensin IV-derived oligopeptide, N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, also called PNB-0408. It was developed at Washington State University. It is not FDA-approved. It is not a GLP-1, GIP, or amylin drug. There is no completed human randomized trial of Dihexa itself. A ClinicalTrials.gov search for Dihexa, PNB-0408, and N-hexanoic returned no interventional efficacy record.
The mechanism story is compromised. Benoist 2014 (HGF/c-Met) is retracted. Kawas 2012 is retracted. McCoy 2013 still carries a 2021 Expression of Concern. Do not treat those Harding/Kawas JPET results as established fact.
Independent work still exists. Sun et al. (Brain Sciences, 2021) reported Morris water maze gains in APP/PS1 mice after 1.44 mg/kg or 2.88 mg/kg Dihexa. Wells et al. (Journal of Huntington's Disease, 2024) reported that PNB-0408 did not protect rats from 3-nitropropionic acid deficits. That is the usable map: one positive Alzheimer's-model mouse study from a Chinese group, one negative Huntington-like rat study, and a retracted WSU mechanism package.
The site already has a short research profile and vendor listings. This explainer is the evidence map those pages do not carry. This is the 10:07 Research Roundup, not an incretin story.
What Dihexa is
PubChem CID 129010512 lists the title N-(1-oxohexyl)-L-tyrosyl-N-(6-amino-6-oxohexyl)-L-isoleucinamide, formula C27H44N4O5, molecular weight 504.7, CAS 1401708-83-5. Synonyms include dihexa, PNB-0408, and N-hexanoic-Tyr-Ile-(6) aminohexanoic amide. Catalogs often cite about 535 Da. This article uses the PubChem record.
McCoy et al. (JPET, 2013, PMID 23055539) name the stabilized analog N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (Dihexa). That paper remains under Expression of Concern (PMID 34551989). Dihexa is sold as a research chemical. It is not approved for human use. It is not Pinealon, Humanin, or FOXO4-DRI.
| Thing | What it is | What a paper can show |
|---|---|---|
| Dihexa / PNB-0408 | Synthetic Ang IV-derived oligopeptide, PubChem 504.7 Da | Rodent behavior, histology, cytokines, PI3K/AKT markers |
| Angiotensin IV | Endogenous hexapeptide in the brain renin-angiotensin system | Class context, not Dihexa efficacy |
| Fosgonimeton (ATH-1017) | Athira small-molecule HGF-pathway modulator | A related clinical program, not a Dihexa trial |
| Research-vendor vial | A catalog chemical sold as Dihexa | Paperwork, not a trial product |
A COA check can test whether a certificate names a real lab. It cannot turn a catalog vial into the Sun 2021 reagent. Dihexa is not approved for human use.
The mechanism integrity problem
Benoist et al., JPET, November 2014 (PMID 25187433). Retracted. The paper claimed that Ang IV-derived peptides, including Dihexa, depend on hepatocyte growth factor and c-Met for "procognitive" and "synaptogenic" effects. The retraction notice (PMID 40312093, doi 10.1016/j.jpet.2025.103567, April 2025) states that a Washington State University investigation found falsified or fabricated data in Figures 1B and 2A/C and in a later erratum submission. The notice says Leen H. Kawas and Joseph W. Harding were solely responsible. Do not treat Benoist 2014 results as established fact. The notice is citable. The retracted findings are not.
Kawas et al., JPET, March 2012 (PMID 22129598). Retracted. NCBI lists the April 2025 notice (PMID 40312092, doi 10.1016/j.jpet.2025.103566) and an earlier Expression of Concern (PMID 34551990). This is the companion HGF/Met package, not an independent confirmation. Do not rely on it for positive claims.
McCoy et al., JPET, January 2013 (PMID 23055539). Still in the literature, with an Expression of Concern from September 2021 (PMID 34551989). The abstract reports scopolamine and aged-rat maze work and "marked synaptogenic activity." A circulating line that Dihexa is about 10 million times, or seven orders of magnitude, more potent than BDNF tracks to this lab's assay-specific in-vitro spine work. That comparison is not a clinical potency.
Ho and Nation (Neuroscience and Biobehavioral Reviews, 2018, PMID 29733881) reviewed experimental Ang IV and Ang-(1-7) studies. A class review does not repair retracted figures.
c-Met is an oncogene-associated receptor in pathway biology. A theoretical concern that chronic HGF/c-Met agonism could matter for cancer risk is a hypothesis from that biology. It is not a demonstrated human cancer signal from Dihexa trials. There are no Dihexa trials.
What the usable papers actually measured
Two primary experimental papers remain usable after the retractions. They disagree.
Sun, Deng, Fu, Wang, Duan, and Zhang, Brain Sciences, 11 November 2021 (PMID 34827486, PMC8615599, doi 10.3390/brainsci11111487). Independent Chinese group at China Pharmaceutical University (Nanjing) and Nanjing First Hospital. Not the WSU Harding/Kawas list.
Six-month-old APP/PS1 mice and age-matched wild-type mice. Part 1: wild-type, APP/PS1 vehicle, APP/PS1 plus Dihexa 1.44 mg/kg, APP/PS1 plus Dihexa 2.88 mg/kg. Part 2: APP/PS1, Dihexa 2.88 mg/kg, and Dihexa 2.88 mg/kg plus wortmannin 0.5 mg/kg. Treatment ran from six to nine months of age, about three months, then Morris water maze.
The methods text does not pick one route. One sentence says Dihexa and wortmannin, in 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, were "administered intragastrically to the APP/PS1 mice." The next says "The Dihexa was administered intraperitoneally to the APP/PS1 mice from six to nine months old." Results later mention "three months of injection" and, for the Ang IV ELISA, 1.44 mg/kg and 2.88 mg/kg "administered intragastrically." This article reports that inconsistency. It does not invent which route is correct.
Versus APP/PS1 vehicle, escape latency fell (especially days four and five), probe-trial crossings rose, Nissl counts and synaptophysin (SYP) rose, astrocyte and microglia markers fell, IL-1β and TNF-α fell, IL-10 rose, and PI3K and phosphorylated AKT rose. Wortmannin 0.5 mg/kg reversed the PI3K/AKT, anti-inflammatory, and anti-apoptotic readouts the authors attributed to Dihexa. They wrote that 2.88 mg/kg recovered nerve cells and function more than 1.44 mg/kg. Those are APP/PS1 mouse numbers. They are not a human result.
Wells, Azzam, Hiller, and Sardinia, Journal of Huntington's Disease, 2024 (PMID 38489193, doi 10.3233/JHD-231507). Whitworth University (Spokane), with Oregon Health and Science University and University of Washington authors. Not the WSU list.
Forty male Wistar rats in three arms: vehicle, 3-nitropropionic acid (3-NP), and 3-NP plus PNB-0408. 3-NP is a mitochondrial toxin used to mimic Huntington-like injury. PNB-0408 was given with chronic 3-NP. Weight, motor function, and cognition were followed for five weeks, then histology. The abstract does not state a PNB-0408 milligram-per-kilogram figure. This article does not invent one.
The result is negative. 3-NP reduced weight gain, impaired spatial learning and memory consolidation, and produced marked motor dysfunction. "From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity."
| Paper | Design | Dihexa / PNB-0408 result |
|---|---|---|
| Sun 2021, Brain Sci | APP/PS1 mice, ~3 months, 1.44 or 2.88 mg/kg, then Morris maze | Positive versus APP/PS1 vehicle on maze, SYP, cytokines, PI3K/AKT |
| Wells 2024, J Huntingtons Dis | 40 male Wistar rats, 3-NP, 5 weeks | Negative. PNB-0408 did not protect. |
| Benoist 2014, JPET | HGF/c-Met dependence, spinogenesis | Retracted April 2025. Not usable as fact. |
| Kawas 2012, JPET | Ang IV analogs as HGF/Met modifiers | Retracted April 2025. Not usable as fact. |
| McCoy 2013, JPET | Chemical stabilization, scopolamine and aged-rat maze | Expression of Concern, September 2021. Flagged. |
A registered interventional human efficacy trial of Dihexa was not identified.
Related class context: fosgonimeton is not Dihexa
Athira Pharma's fosgonimeton is a small-molecule HGF-pathway positive modulator. It is a Dihexa-related clinical program, not Dihexa. PubChem lists ATH-1001 among Dihexa synonyms. Fosgonimeton was developed as ATH-1017. Do not collapse those names.
On 3 September 2024 Athira reported LIFT-AD (NCT04488419) topline results. The company said once-daily subcutaneous fosgonimeton at 40 mg was evaluated in 312 mild-to-moderate Alzheimer's patients not on acetylcholinesterase inhibitors, over 26 weeks. The primary Global Statistical Test (ADAS-Cog11 plus ADCS-ADL23) and those two key secondaries missed statistical significance versus placebo. Reuters reported the same-day miss.
That failure is class context. It is not a Dihexa human trial. A related HGF-modulation program missing its Alzheimer's endpoints does not prove Dihexa would fail in people. It also does not rescue retracted WSU figures.
Research exposures reported in animals
Dihexa is not approved for human use. The table reports laboratory exposures. It is not a dosage guide or a consumer protocol.
| Setting | Reported exposure | Source |
|---|---|---|
| APP/PS1 mice, Part 1 | 1.44 mg/kg or 2.88 mg/kg Dihexa, six to nine months of age, about three months | Sun et al., 2021 |
| APP/PS1 mice, Part 2 | 2.88 mg/kg Dihexa, with or without wortmannin 0.5 mg/kg | Sun et al., 2021 |
| Sun 2021 vehicle (study solvent, not a protocol) | 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline | Sun et al., 2021 |
| Sun 2021 route language | Methods state both intragastric and intraperitoneal wording; results mention injection and intragastric ELISA dosing | Sun et al., 2021 |
| 3-NP Huntington-like rats | PNB-0408 given with chronic 3-NP for a five-week observation window. No mg/kg figure in the PubMed abstract. | Wells et al., 2024 |
| Fosgonimeton LIFT-AD (not Dihexa) | 40 mg subcutaneous daily, 26 weeks, n = 312 in the company topline | Athira, 3 September 2024 |
That does not make 2.88 mg/kg an approved dose. Mouse milligrams-per-kilogram are not a human milligram conversion. No anecdotal human-equivalent translation appears here. The Sun solvent is a study vehicle, not a reconstitution protocol.
What this does not mean
- It is not human efficacy or an approved cognitive drug. No identified RCT gave Dihexa to people. FDA has not approved it.
- Benoist 2014 and Kawas 2012 are not mechanism proof. Both are retracted. McCoy 2013 is under Expression of Concern. The circulating "10 million times BDNF" line is an assay claim from that flagged spine package, not a clinical potency.
- Sun 2021 maze gains are not a human memory result. The paper also does not resolve its own intragastric versus intraperitoneal wording.
- Wells 2024 is a 3-NP rat failure. It blocks a simple "neuroprotective in neurodegenerative models" slogan. It does not prove Dihexa never works in any animal system.
- LIFT-AD is not a Dihexa trial. Fosgonimeton missed GST, ADAS-Cog11, and ADCS-ADL23.
- c-Met cancer risk is not a Dihexa trial finding. There are no Dihexa trials. Pathway biology can raise a hypothesis. It cannot report a human signal that was never measured.
- A research-vendor listing is not the study product. This is not medical advice, not a consumer protocol, and not an incretin story.
Related maps stay on their own molecules: Pinealon, Humanin, FOXO4-DRI, and ARA-290.
Limitations
Dihexa's unapproved status did not change on 9 September 2026. The research profile was not rewritten. Live listings remain catalog chemicals. Nobody in the usable primary papers received Dihexa in a controlled human trial.
Sun 2021 is one APP/PS1 mouse paper. Its methods state both intragastric and intraperitoneal administration. That is a reporting defect, not a detail to smooth over. Wells 2024 is a 3-NP toxin model, not genetic Huntington's disease, and the fetched abstract does not give a PNB-0408 dose. The Harding/Kawas JPET trio cannot carry positive mechanism weight after two retractions and one Expression of Concern. Theoretical c-Met language is pathway inference. The 504.7 versus ~535 dalton discrepancy is not settled by a maze paper.
What to watch
- A first registered interventional human protocol for Dihexa itself. Until one exists, Dihexa stays preclinical.
- Whether later APP/PS1 replications state one route and one vehicle. Sun 2021 cannot be reread as a clean oral or intraperitoneal study until that wording is resolved.
- Independent in-vivo work that does not share the retracted WSU figures. Wells 2024 already shows the analog does not travel to every injury model.
- Any attempt to treat Benoist 2014 or Kawas 2012 as live evidence. NCBI marks both retracted.
- How vendors describe potency versus BDNF. Assay-spine language from a flagged paper is not a sterility claim. Check whether a certificate names Dihexa or PNB-0408 and a real lab.
FAQs
What is Dihexa?
A synthetic angiotensin IV-derived oligopeptide (PNB-0408). PubChem CID 129010512 lists C27H44N4O5, 504.7 Da, CAS 1401708-83-5. It is not FDA-approved.
Has Dihexa been tested in a human RCT?
No. ClinicalTrials.gov had no Dihexa, PNB-0408, or N-hexanoic interventional record in the search used here.
Did it treat Alzheimer's or Huntington's disease in people?
No. Sun 2021 treated APP/PS1 mice. Wells 2024 reported no protection in a 3-NP rat model. LIFT-AD tested fosgonimeton, not Dihexa.
What dose was used?
Sun 2021 reported 1.44 mg/kg and 2.88 mg/kg in mice for about three months. Wells 2024 did not state a PNB-0408 mg/kg figure in the PubMed abstract. That does not make 2.88 mg/kg an approved dose.
Is the HGF/c-Met mechanism established?
No. Benoist 2014 and Kawas 2012 are retracted. McCoy 2013 remains under Expression of Concern.
This article is for general informational purposes only and is not medical advice. Talk to a licensed clinician about personal medical decisions. Dihexa is an investigational synthetic oligopeptide studied in mice and rats. Nothing here is a dosing protocol or a recommendation to obtain an unapproved product.
Continue your research
Sources
- Sun et al. Brain Sci. 2021;11(11):1487. PMID 34827486
- Wells et al. J Huntingtons Dis. 2024;13(1):55-66. PMID 38489193
- Retraction notice for Benoist 2014. J Pharmacol Exp Ther. 2025. PMID 40312093
- Retraction notice for Kawas 2012. J Pharmacol Exp Ther. 2025. PMID 40312092
- McCoy et al. J Pharmacol Exp Ther. 2013;344(1):141-154. PMID 23055539
- Expression of Concern for McCoy 2013. PMID 34551989
- Ho and Nation. Neurosci Biobehav Rev. 2018;92:209-225. PMID 29733881
- PubChem CID 129010512. Dihexa / PNB-0408. CAS 1401708-83-5
- ClinicalTrials.gov search for Dihexa (no interventional hits in this review)
- Athira LIFT-AD topline, 3 September 2024
- Reuters. Athira Alzheimer's drug fails mid-to-late stage trial. 3 September 2024
- ClinicalTrials.gov NCT04488419 (LIFT-AD, fosgonimeton, not Dihexa)