F tier · safety concern
Dihexa has never been tested in a human. The two papers that created it and characterised its mechanism — the 2012 development of angiotensin IV analogues as hepatocyte growth factor/Met modifiers and the 2014 demonstration that the procognitive effect depends on the HGF/c-Met system — were both retracted by the Journal of Pharmacology and Experimental Therapeutics. Four papers from the same author carried expressions of concern from September 2021, and in January 2025 Athira Pharma paid $4 million to settle US Department of Justice allegations that the author altered images in her dissertation and in at least four papers published between 2011 and 2014. The mechanism dihexa is sold on rests on retracted work, and no human evidence exists to replace it.
dihexa
Dihexa is a small, orally bioavailable angiotensin IV analogue developed at Washington State University and reported to enhance hepatocyte growth factor signalling through the c-Met receptor, with rodent studies describing marked dendritic spine formation. Its core supporting literature has since been retracted, no human trial has ever been conducted, and the mechanism it claims is a well-established cancer proliferation pathway.
// we supply this one
available as a research reagent
≥ 98% HPLC · lyophilised powder · batch certificate published. Grade F above is our own and is not adjusted because we stock it.
the explanation
Dihexa is an experimental compound that was supposed to help brain cells form new connections, and early rat studies looked dramatic. The two studies that made its name were formally withdrawn by the journal in 2025 after image problems were found, it has never been tested in a single human, and the pathway it targets is one that tumours use to grow.
regulatory status
Unapproved investigational compound
Dihexa has no approval from any regulatory authority anywhere in the world, has never entered a registered human clinical trial, and is not a recognised investigational medicinal product — unlike Semax and Selank it does not even hold a national registration. FDA has scheduled a Pharmacy Compounding Advisory Committee meeting before the end of February 2027 to consider whether this substance should be added to the section 503A bulks list. A committee recommendation is non-binding and confers no approval; implementation would require notice-and-comment rulemaking, which the FDA bar estimates at twelve to twenty-four months or longer.
how it works · proposed mechanism
Dihexa's proposed mechanism is now difficult to state with confidence because the papers that established it have been withdrawn.
Claimed HGF/c-Met activation
Dihexa was reported to bind hepatocyte growth factor and potentiate signalling through its receptor c-Met, driving synaptogenesis. The 2012 paper that established this mechanism was retracted in 2025.
Reported spine formation
Rodent work described a near-threefold increase in dendritic spines, roughly 41 versus 15 per 50-micrometre segment, with wider spine heads. This finding came from the body of work now subject to retraction.
c-Met is an oncology target
HGF/c-Met is one of the best-characterised proliferation and metastasis pathways in oncology, and receptor overexpression correlates with poorer cancer prognosis. Drug development against c-Met overwhelmingly aims to inhibit it, not activate it.
Very long rodent half-life
Reported elimination half-life in rats was roughly 12.7 days intravenously and 8.8 days intraperitoneally, extraordinarily long for a small peptide-derived molecule. This implies substantial accumulation with repeated exposure and no rapid off-ramp if harm emerged.
what’s reported
evidence shape
6 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
c-Met activation is a known oncology proliferation pathway — the HGF/c-Met axis drives tumour growth and metastasis, receptor overexpression predicts worse cancer outcomes, and there are zero human trials of Dihexa establishing any safety margin against that risk. Worse, the two Journal of Pharmacology and Experimental Therapeutics papers that established both the mechanism and the procognitive effect were retracted in April 2025 after image-manipulation findings against a co-author, so the compound's central claims now rest on withdrawn evidence.
key published findings
- RETRACTED — rodent/in vitro: the 2012 paper reporting development of angiotensin IV analogs as HGF/Met modifiers, which established Dihexa's mechanism, was retracted by JPET in April 2025
- RETRACTED — rodent: the 2014 paper reporting that procognitive and synaptogenic effects of angiotensin IV-derived peptides depend on HGF/c-Met activation was retracted by JPET in April 2025
- Research integrity: four JPET papers (2011-2014) co-authored by Leen Kawas during her doctoral work at Washington State University received expressions of concern in 2021 over possible image manipulation; investigators found images had been altered in her dissertation and at least four papers
- Human trial (closest analogue): fosgonimeton (ATH-1017), Athira Pharma's HGF/MET positive modulator developed from this same Washington State University angiotensin IV programme, failed to meet its primary endpoint in the Phase 2/3 LIFT-AD trial in mild-to-moderate Alzheimer's disease
- Rodent (pre-retraction, as reported): dendritic spine density approximately 41 versus 15 per 50-micrometre dendrite segment, with spine-head width 0.80 versus 0.67 micrometres, and cognitive improvement in scopolamine-impaired rats at 0.5-2.0 mg/kg
limitations of the evidence
- The primary evidence base has been formally retracted, meaning the mechanism and efficacy claims cannot currently be cited as established science
- No human trial of any phase has ever been conducted, so there is no human safety, pharmacokinetic, or dose-response data whatsoever
- No long-term carcinogenicity or tumour-promotion study exists in any species despite the mechanism directly implicating a proliferation pathway
- Both foundational dihexa papers have been retracted by the journal that published them, following a federal data-falsification settlement involving their author.
documented safety signals
- HGF/c-Met activation is a validated oncogenic proliferation and metastasis pathway; theoretical tumour-promotion risk is explicitly flagged in independent review
- Exceptionally long rodent half-life (~12.7 days IV) implies accumulation with repeat exposure and no rapid clearance if harm emerged
- Zero human safety data at any dose or duration
- No carcinogenicity testing performed in any species
identity
| full name | N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide |
| category | Cognitive |
| modality | small molecule |
| formula | C27H44N4O5 |
| molar mass | 504.7 g/mol |
| cas | 1401708-83-5 |
| half-life | ~12.7 days (rat, intravenous); ~8.8 days (rat, intraperitoneal) |
| sequence | N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide (modified tripeptide, not a standard peptide sequence) |
laboratory handling
| storage | Lyophilised powder stable at -20°C protected from light and moisture; reconstituted solutions should be held at 2-8°C for short-term use or aliquoted at -20°C, avoiding repeated freeze-thaw cycles. |
| solubility | Poorly water-soluble; laboratory preparations typically use DMSO as primary solvent, sometimes with subsequent dilution into aqueous buffer. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
8 citedJournal of Pharmacology and Experimental Therapeutics · 2025 · peer-reviewed
Journal of Pharmacology and Experimental Therapeutics · 2025 · peer-reviewed
Retraction Watch · 2021 · review
Journal of Alzheimer's Disease · 2015 · review
Progress in Neurobiology · 2015 · review
Alzheimer's Drug Discovery Foundation · 2020 · review
Retraction Watch · 2025 · news
U.S. Food and Drug Administration · 2026 · regulatory
others in Cognitive