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safety record

Dihexa: what has been measured about safety

The safety record for dihexa, read as a record: the agency statement that anchors it, what the rodent studies were actually designed to measure, and the question the target carries with it.

Last Reviewed Editorial policy Methodology

One agency has put a position on dihexa in writing, and it is the most useful sentence available about this compound. FDA lists dihexa acetate among bulk drug substances for use in compounding that may present significant safety risks, and its stated reasoning is that it has identified no human exposure data on drug products containing the substance by any route of administration, and that it lacks important information regarding any safety issues raised by it, including whether it would cause harm if administered to humans [12].

Read that in both directions, because it gets read in one direction at a time. It is not a finding that the compound harmed anyone: the agency is describing an empty file rather than a full one. And it is not permission to assume the file is empty because there is nothing to find, because nobody has looked.

What exists instead is rodent work built to measure behaviour, a laboratory target with a substantial cancer literature attached to it, and two publication flags on the papers underneath the mechanism the compound is sold for. This page sets out all four.

Not medical advice

This page reports what has been documented about a compound. It is not medical advice, not a diagnosis, not a dosing protocol, and not a recommendation to obtain or use anything described here. Talk to a licensed clinician about anything concerning your health. Read the full disclaimer.

Reviewed against editorial standards Updated

What this page reports, and what it does not

We report what has been documented. We do not prescribe what should be done.

Every sentence below reports what a named source measured or searched, in what system, and what it found. Where the answer is that nobody has looked, the page says which study would have looked and names the document recording that it was not done.

This page publishes no dose, no schedule, no route instruction and no list of people who should avoid anything. A list of who should not use a compound is a directions-for-use document, and it only makes sense if the reader is going to use the thing. What replaces it is a description of the compound and its record, written about the molecule rather than about the reader.

What has been measured

The agency statement, quoted rather than summarised

FDA's category 2 table carries a row for dihexa acetate, and the row's own words are worth reproducing rather than paraphrasing. FDA has not identified any human exposure data on drug products containing dihexa acetate administered via any route of administration. FDA lacks important information regarding any safety issues raised by dihexa acetate, including whether it would cause harm if administered to humans. The page content was current as of 22 April 2026 and was read on 23 August 2026 [12].

That is a statement about what the agency could find, and it is the same shape as the absences elsewhere on this page. It sets a ceiling on everything a reader can be told: a substance with no human exposure data cannot have its risks in people described, by this site or by anyone selling it.

It is also the whole of the regulatory record on this compound's safety. No agency has approved it, none has evaluated it in any other proceeding, and no investigational application for it appears on the public record.

What the rodent studies measured, and what they were built for

Two current rodent studies name an angiotensin IV analog and report what the animals did. A 2021 study in the APP/PS1 transgenic mouse, a model engineered to develop amyloid pathology, reports recovery of memory and implicates PI3K and AKT signalling [3]. A 2024 study gave rats 3-nitropropionic acid, a chemical that produces symptoms resembling Huntington's disease, and measured the analog's effect on them [4].

Both were designed to measure behaviour, and that design decides what they can report. A behavioural study observes the animals over its own period and notes what happened to them; it does not collect serum chemistry, organ weights or histopathology on a schedule, and it is not powered to detect anything uncommon. An observation made in passing inside an experiment built for something else is not a toxicology result.

So the honest description of the animal record is that it exists and answers a different question. The study types that answer a safety question, the acute and repeat-dose toxicity studies, were not located in the literature behind this review for this compound in any species. [Animal] [3] [4]

The question the target carries

The hepatocyte growth factor and c-Met system is the mechanism this compound is sold on, and it is a system laboratories use to drive cells to divide and to change type. Two published protocols use small molecules acting on it to push human pluripotent stem cells toward becoming liver cells [5] [6], which is what that system does when it is switched on deliberately.

That is what makes unwanted growth a standard question to ask about anything aimed at this target: a system used deliberately to make cells divide and change type is one where the question arises on its own. This page names no source for a cancer risk and asserts none, because no study of this compound has looked at it in any system. What it records is that the question is standard and that nothing on the public record asks it here. [In-vitro] [5] [6]

Why the publication flags reach a safety question too

Two papers underneath this compound carry notices. The 2014 paper reporting that the procognitive and synaptogenic effects of angiotensin IV-derived peptides depend on activation of the hepatocyte growth factor and c-Met system was retracted in April 2025, after carrying an expression of concern from September 2021 [1] [10]. The 2013 paper evaluating the analog series, which is where potency comparisons within the series come from, still carried its own expression of concern when this page was reviewed [2].

This site did not establish the reason for the retraction: the notice carries no abstract in PubMed and the publisher's page did not return a document, so no reason is stated here and none should be inferred [10].

The reason that belongs on a safety page rather than only on the main review is narrow. A safety question about a compound is usually approached through its mechanism, and the published statement of this compound's mechanism has been withdrawn from the record. Reasoning about what a molecule might do, starting from a paper that is no longer part of the evidence base, produces an answer with nothing under it.

What the trials on the same target do not cover

Fosgonimeton is a different molecule aimed at the same hepatocyte growth factor and c-Met system, and it went through six registered trials including a Phase 2/3 in 554 people. Those trials produced human exposure to that molecule under a protocol, with monitoring and reporting attached.

None of it is exposure to this compound. A trial of one molecule is not a trial of another, however closely the two are related, and that separation runs in the safety direction exactly as it runs in the efficacy direction. What the fosgonimeton programme measured and did not report is set out, with its sources, on the fosgonimeton safety record, linked under Safety records this page refers to at the foot of this page.

What has not been characterised

Set out plainly, so the shape of the gap is visible rather than implied. Nothing is published on what a single large exposure to this compound does, what daily exposure does over weeks or months, whether the molecule affects DNA, what it does in pregnancy or to offspring, or whether lifetime exposure produces tumours. FDA's own search found no human exposure data by any route [12], and the registry sweep on 23 August 2026 found no registration at any phase, in any country, for any indication [11].

Nothing is published on the route the compound is generally sold for, which is by mouth or under the tongue. There is no human half-life, no exposure figure and no route comparison, because no human study of any design has been run. Nothing is published on interaction with any other substance either.

Two things follow from that, and only two. This page cannot describe the risks of dihexa, because the studies that would describe them do not exist. And nobody else can describe them either, from the same absence, whatever a product page says.

Our takeThe sentence most worth carrying away from this page is FDA's, and it is usually quoted with one half missing. The agency says it has identified no human exposure data for this substance by any route, and that it lacks the information to know whether the substance would cause harm if administered to humans. Neither half is a warning and neither half is a clearance. It is a description of an empty file, written by the one body that went looking.

Talk to a licensed clinician about anything concerning your health.

Frequently asked questions

Is dihexa safe?

Nobody can answer that from published evidence, and this site does not answer it from anything else. FDA states that it has identified no human exposure data on products containing dihexa acetate by any route, and that it lacks important information regarding any safety issues raised by it, including whether it would cause harm if administered to humans [12]. That is an absence of measurement rather than a measurement of absence.

Are there any reported side effects of dihexa?

None are on the public record, and the reason matters more than the fact. No registered trial of this compound has ever been run [11], so there is no protocol under which an adverse event would have been collected and no surveillance system this material reports into. A null result from a system nobody reports into measures the reporting.

Does dihexa affect the liver or the kidneys?

Nothing published measures either. The study type that collects liver enzymes, kidney markers, organ weights and histology is the repeat-dose toxicity study, and no such study of this compound was located for this page in any species. The rodent studies that exist measured behaviour in a transgenic mouse [3] and in a chemically injured rat [4], so there is no liver or kidney observation to report in either direction.

Does dihexa cause cancer?

No study has tested it, and no carcinogenicity study of this compound was located. There is a question worth stating precisely. The hepatocyte growth factor and c-Met system this compound is sold to act on is used in laboratories to drive cells to divide and to change type [5] [6], which is what makes unwanted growth a standard question to ask about anything aimed at it. This page names no source for a cancer risk and asserts none. Nothing published asks the question for this compound, in either direction.

Does the retracted paper mean the compound is dangerous?

No, and the retraction says nothing in that direction. A retraction removes a paper from the body of published evidence; it is not a finding about a molecule. This site did not establish why the 2025 retraction was issued, because the notice carries no abstract in PubMed and the publisher page did not return a document [10]. What the retraction does mean is that the mechanism account a safety argument would start from is no longer part of the record.

Do the fosgonimeton trials tell us anything about dihexa's safety?

Not as evidence about this compound. They are trials of a different molecule aimed at the same system, and human exposure to one molecule is not human exposure to another. The fosgonimeton record has its own page and its own sources, linked at the foot of this one.

What would change what this page says?

A published toxicology study in any species would, and it would be the first. So would a registered human trial of any design, since there is none. An adverse event report reaching a surveillance system this material actually reports into would too, and today no such channel exists for a compound sold as a research chemical.

References

  1. Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014. PMID 25187433 DOI 10.1124/jpet.114.218735 Retracted April 2025 (retraction notice PMID 40312093); carried an Expression of Concern from September 2021 (J Pharmacol Exp Ther 2021;378(3):311). Cited here as the record of what was claimed and what happened to it, not as evidence.
  2. McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, Harding JW. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013. PMID 23055539 DOI 10.1124/jpet.112.199497 Carries an Expression of Concern published September 2021 (J Pharmacol Exp Ther 2021;378(3):313), still standing as read on 23 August 2026.
  3. Sun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. Brain Sci. 2021. PMID 34827486
  4. Wells RG, Azzam AF, Hiller AL, Sardinia MF. Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats. J Huntingtons Dis. 2024. PMID 38489193
  5. Siller R, Greenhough S, Naumovska E, Sullivan GJ. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Reports. 2015. PMID 25937370
  6. Mathapati S, Siller R, Impellizzeri AA, Lycke M, Vegheim K, Almaas R, Sullivan GJ. Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol. 2016. PMID 27532814
  7. Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol. 2015. PMID 25455861 A review by the originating group.
  8. Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neurosci Biobehav Rev. 2018. PMID 29733881
  9. Wright JW, Harding JW. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015. PMID 25649658 A review by the originating group.
  10. Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW. Retraction notice to "The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System" [J Pharmacol Exp Ther 351 (2014) 390-402]. J Pharmacol Exp Ther. 2025. PMID 40312093 DOI 10.1016/j.jpet.2025.103567 Read via PubMed on 23 August 2026; the notice carries no abstract there and the publisher page did not return a document, so the stated reason for the retraction was not obtained.
  11. ClinicalTrials.gov. Registry sweep for dihexa, PNB-0408 and N-hexanoic-Tyr-Ile-(6) aminohexanoic amide across the intervention and free-text fields, run through the v2 API on 23 August 2026. No record returned at any phase, in any country, for any indication. ClinicalTrials.gov. 2026. ClinicalTrials.gov
  12. US Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks. The category 2 table carries the row Dihexa acetate, reading: FDA has not identified any human exposure data on drug products containing dihexa acetate administered via any route of administration; FDA lacks important information regarding any safety issues raised by dihexa acetate, including whether it would cause harm if administered to humans. Page content current as of 22 April 2026, fetched with a browser user agent and read on 23 August 2026. Appended on 2026-08-23, when this page's regulatory section was corrected: it had stated that no agency had evaluated this compound. FDA human drug compounding. 2026. FDA category 2 list