Dihexa

What it is

Dihexa, also written as PNB-0408, is a small synthetic molecule built from angiotensin IV. Its full chemical name is N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, and it carries CAS number 1401708-83-5. The modifications at either end of the molecule are what make it stable enough to survive in the body and small and fatty enough to cross into the brain, and they are also what make it a laboratory construct rather than something the body produces. It is not an endogenous peptide, and pages that describe it as one are wrong on the first line.

It came out of a research programme at Washington State University led by Joseph Harding, who invented the compound. It is not approved by the FDA for anything. It is not a drug, it is not a dietary supplement, and it is not on the list of substances eligible for pharmacy compounding. It is sold on the research-chemical market, and it is also administered by some private clinics, which is worth stating plainly because it is the market a reader of this page is shopping in.

What is claimed for it

The claims are unusually specific for a research compound, which is part of why they travel so well. Dihexa is described as a potentiator of hepatocyte growth factor and its receptor c-Met, a pathway involved in building new synaptic connections. It is said to promote synaptogenesis, to reverse cognitive deficits, to work when taken orally, and to be seven orders of magnitude more potent than brain-derived neurotrophic factor.

That last number is the one doing most of the marketing work, and it is worth knowing where it came from. The Alzheimer's Drug Discovery Foundation checked it and found it does not appear in the underlying publication at all. It originated in a press release, and Dihexa and BDNF were never directly compared in the published work. [5] A figure repeated on nearly every vendor page turns out not to have been a finding.

What happened to the evidence

This is the section that makes Dihexa different from anything else on this site. Most research peptides have thin evidence. Dihexa's foundational evidence was withdrawn by the journal that published it.

• The mechanism paper, retracted April 2025 The 2012 paper in the Journal of Pharmacology and Experimental Therapeutics that established angiotensin IV analogues as HGF/Met modifiers was retracted at the editors' request. Following an investigation at Washington State University, two of its figures were found to contain falsified or fabricated data. [1] This is the paper that made the mechanism a mechanism.
• The dependence paper, also retracted April 2025 The 2014 paper reporting that the procognitive and synaptogenic effects of these peptides depend on the HGF/c-Met system was retracted for the same reason, with figures and data submitted in a subsequent erratum found to be falsified or fabricated. The investigation named Leen Kawas and Joseph Harding as solely responsible. [2] This paper is the source of the binding constant, the dimerization claim, and the knockdown experiments that supposedly proved the effect runs through HGF. If a vendor page shows a diagram of Dihexa acting on HGF and c-Met, it is drawing on a withdrawn paper.
• The efficacy paper, flagged but not retracted The 2013 paper evaluating metabolically stabilized angiotensin IV analogues is the source of essentially every efficacy number in circulation: oral activity at 2 mg per kilogram per day, the reversal of scopolamine-induced impairment in the Morris water maze, the aged-rat result, the roughly threefold increase in dendritic spines, and the blood-brain-barrier and half-life data. It has carried an editorial Notice of Concern since 2021. [3] A Notice of Concern is not a retraction, and this page does not treat it as one. But a reader deciding whether to inject something is entitled to know the paper is flagged.

Two mistakes are easy to make here and both should be avoided. The first is repeating the claim, which circulates in secondary write-ups, that the HGF-mimetic mechanism has since been independently replicated. We could not source that claim to a named independent group and it does not belong on a page like this until someone can. The second is the mirror image: retraction of a mechanism paper is not proof that a compound does not work. Dihexa has not been shown not to work. It has never been properly tested. The accurate position is narrower than either of those and more interesting than both.

What was tested in humans

For Dihexa itself, nothing. There is no registered clinical trial of Dihexa, no Phase 1, no published human pharmacokinetics, and no published human safety data of any kind. [5]

The pathway did get its shot in humans, though, through a successor compound from the same programme, and that story is the most useful thing on this page. Fosgonimeton, also called ATH-1017, came out of the same Washington State University work by way of a spin-out that became Athira Pharma. It is worth being careful about the relationship: secondary sources routinely call fosgonimeton a prodrug of Dihexa, while Alzforum, which asked the company directly, puts it more cautiously as a related compound that further development led to. [6] Successor compound from the same programme is the description this page can stand behind.

• Phase 1: clean, and it measured the wrong thing for our purposes Eighty-eight subjects, across single ascending doses in healthy young men and multiple ascending doses in healthy elderly volunteers and Alzheimer's patients. Safe and well tolerated at all doses, dose-proportional pharmacokinetics, no accumulation over nine days. [4] The trial included no cognitive assessments. Its positive readouts were quantitative EEG gamma power and evoked-potential latency, which are measures of the drug reaching its target, not measures of anyone thinking better.
• Phase 2/3: it failed LIFT-AD was a randomized, double-blind, placebo-controlled trial of daily subcutaneous fosgonimeton in people aged 55 to 85 with mild to moderate Alzheimer's disease. [8] The primary analysis population was the 312 participants who were not taking an acetylcholinesterase inhibitor. The primary endpoint, a global statistical test combining cognition and function, moved by 0.08 points, at p equal to 0.70. Cognition and function measured separately also failed to reach significance, at p equal to 0.35 and 0.61. The sponsor attributed the result partly to a lack of decline in the placebo arm and to study duration. [7] Fosgonimeton was not carried forward, and the company's remaining in-house candidate is a different, next-generation compound. [9]

So the HGF and c-Met mechanism was tested at proper scale, in the right population, with a real endpoint, and it did not work. That is worth more to a reader than any quantity of rodent data, and it is a fact absent from every vendor page we have seen.

The problem for the people who actually buy it

Dihexa is sold as a nootropic to people with ordinary cognition. Every positive animal result is a reversal of a deficit, either induced with scopolamine or arising from age. In cognitively normal animals, Dihexa did not improve cognitive function. [5]

That is not a subtle limitation to note at the bottom of a page. The population the compound is marketed to is precisely the population in which it has never shown a benefit, in any species.

Safety, and the gap where the data should be

The Alzheimer's Drug Discovery Foundation's review is blunt about this: no studies in animals or in humans have examined the long-term safety of Dihexa. [5] Three specifics deserve their own lines.

• The half-life is extraordinary and the human figure is unknown In rats, roughly 12.7 days given intravenously and 8.8 days given intraperitoneally. [3] [5] The human half-life has not been measured. A compound taken daily with a half-life measured in weeks accumulates, and nobody has established what that plateau looks like in a person.
• The oncology concern is structural rather than theoretical c-Met is an oncogene. Overexpression of HGF and MET signalling is associated with tumour growth, metastasis and worse prognosis, and the entire clinical oncology effort around this pathway is built on inhibiting it. Dihexa is a systemically available, brain-penetrant agonist of that same pathway, and it has never been tested for tumour promotion in any species over any duration. The sponsor's own trials of the successor compound excluded anyone with a malignant tumour diagnosed within three years of screening, and its open-label study excluded anyone newly diagnosed. [8] [5] A company that understood this pathway wrote that exclusion into its protocol.
• It is difficult to get into solution The rodent work dosed Dihexa suspended in 75 percent DMSO. [3] [5] Solubility is a practical problem with this molecule, and anyone reconstituting it will meet the same wall the researchers did.

Typical research parameters

Where that leaves the compound

There is no current authoritative review of Dihexa. The two best independent write-ups, from the Alzheimer's Drug Discovery Foundation and Alzforum, both predate the 2025 retractions and the failure of the successor compound, so both read more favourably than the present facts support. [5] [6] That gap is worth naming: the last time anyone independent and credible assessed this compound carefully, the papers underneath it had not yet been withdrawn.

Related research notes