Dihexa
A small modified dipeptide built from angiotensin IV to reach the brain by mouth: it improved memory in rodent models, but no human has taken it in a published study, and the paper that tied it to the HGF/c-Met growth-factor system is retracted.
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, PNB-0408) was designed at a university lab as a stable, brain-penetrant version of an angiotensin IV fragment. Rat and mouse studies reported better learning and new synapses, and it is sold online as a nootropic. The evidence stops at animals, and a 2024 rat study of a Huntington's-like disease found it did not help.
What is it?
Angiotensin IV is a six-amino-acid fragment of the hormone system that controls blood pressure, and since the 1990s researchers have reported that it and related peptides improve learning in rodents. Peptides like it break down quickly and do not cross from the gut into the blood or from the blood into the brain, so a group including Jay Wright and Joseph Harding, whose later reviews describe the work, set out to shrink and protect it. A 2013 paper described the result: they found the activity of the analogue Nle1-angiotensin IV lived in its first three amino acids, then modified that fragment step by step into an orally active, metabolically stable compound that crosses the blood-brain barrier. They named it dihexa, after the two hexanoic groups at its ends. Despite being sold as a peptide, it is a modified dipeptide: two amino acids, tyrosine and isoleucine, capped at both ends.
In that 2013 paper dihexa reversed memory deficits caused by the drug scopolamine and improved performance in aged rats in a water-maze test, and it increased new synapse formation in the hippocampus. A 2014 paper from the same group then proposed how: that dihexa binds hepatocyte growth factor (HGF) and boosts signalling through its receptor, c-Met, which drives the growth of new dendritic spines and synapses. That mechanism became the basis of dihexa's reputation online. PubMed now lists the 2014 paper as a retracted publication, and two earlier papers from the same group on angiotensin IV analogues as HGF/Met modifiers are also listed as retracted.
Independent work since then is thin. A 2021 study from another group found dihexa restored spatial learning in APP/PS1 mice, a model of Alzheimer's amyloid, reduced inflammation and increased a synapse marker, and traced these effects to the PI3K/AKT pathway rather than to HGF. A 2021 rat study tested it with stem cells and G-CSF after sciatic nerve repair, where the stem cell combinations drove the functional gains. A 2024 study in rats given a mitochondrial toxin that mimics Huntington's disease found it did not protect them from weight loss, learning deficits or motor problems.
No published study has given dihexa to a person, so there is no human dose, safety record or pharmacokinetic data. It is not approved anywhere. In the United States it was in 503A Category 2 until the nomination was withdrawn in April 2026, it is in no category now, so pharmacies cannot compound it, and FDA's advisory committee is slated to review it by the end of February 2027 with no date set. What is sold online is an unregulated research chemical.
Mechanism of Action
How dihexa works is less settled than its reputation suggests. Its developers proposed that it amplifies hepatocyte growth factor signalling through c-Met, but the paper making that case is retracted; the one independent mechanistic study pointed to the PI3K/AKT pathway.
A stabilised angiotensin IV fragment
Dihexa was built from the first three amino acids of Nle1-angiotensin IV, modified at both ends to resist breakdown and cross the gut and blood-brain barriers (2013). The receptor angiotensin IV acts on in the brain is itself disputed, as the developers' 2015 review describes.
HGF/c-Met: proposed, then retracted
The 2014 paper reporting that dihexa binds HGF and enhances c-Met signalling to build synapses is listed as retracted in PubMed, as are two related papers from 2011 and 2012. Their developers' 2015 reviews rest on that work.
PI3K/AKT in an Alzheimer's mouse model
In APP/PS1 mice, dihexa activated PI3K/AKT signalling, and the PI3K inhibitor wortmannin reversed its anti-inflammatory and anti-apoptotic effects (2021). This came from a group not involved in its development.
Brain inflammation
In the same mice it reduced astrocyte and microglia activation, lowered IL-1β and TNF-α and raised IL-10. No human study has measured any of these.
Published Research
Our evidence set holds 17 papers that name dihexa, including in their abstracts. Only two name it in their titles and have an abstract, and both are carded below; both are rodent studies from 2021. Its founding 2013 paper, two 2015 reviews by its developers and a 2024 rat study name it only in their abstracts, so they are listed under References without cards. The retracted 2014 paper is described in the text and not cited as support.
Alzheimer's model mice
In APP/PS1 mice, oral dihexa at several doses increased angiotensin IV in tissue, restored spatial learning in the Morris water maze and increased neurons and the synapse protein synaptophysin. It reduced astrocyte and microglia activation and IL-1β and TNF-α, raised IL-10, and activated PI3K/AKT; the PI3K inhibitor wortmannin reversed its anti-inflammatory and anti-apoptotic effects.
Sciatic nerve repair, rats
In a rat sciatic nerve transection-and-repair model with ten groups of 6 to 8 rats, mesenchymal stem cells, G-CSF and dihexa (2 to 4 mg/kg) were given locally, systemically or into the calf muscle. Sensory function recovered almost fully by eight weeks in all groups; motor function at 8 to 16 weeks improved significantly with stem cells plus G-CSF or stem cells plus dihexa.
Dosing Data
Dihexa has no approved dose and no human dose from any study. Rodent studies gave it by mouth or by injection in doses chosen for animals, such as 2 to 4 mg/kg in the nerve-repair study; those doses do not translate into a human dose.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
There is no human safety data. The animal studies above did not report side effects in their abstracts.
Contraindications & Cautions
With no human studies, these cautions follow from what is and is not known.
Legal Status
Dihexa is not approved as a medicine anywhere and has never been tested in people.
Frequently Asked Questions
?Has dihexa been tested in humans?
Not in any published study we could find. Everything known about it comes from rats and mice, so there is no human dose, safety record or pharmacokinetic data.
?Is the dihexa research reliable?
Partly not. The 2014 paper that tied dihexa to hepatocyte growth factor and its receptor c-Met is listed by PubMed as retracted, as are two related papers from the same group. The 2013 paper that introduced dihexa is not retracted, and a 2021 study by another group found memory benefits in Alzheimer's model mice through a different pathway.
?Is dihexa a peptide?
Loosely. It is two amino acids, tyrosine and isoleucine, capped with a hexanoic acid at one end and an aminohexanoic amide at the other. The name comes from those two hexanoic groups, not from six amino acids.
?Does dihexa work for Alzheimer's disease?
It has not been tested in people with Alzheimer's disease. In APP/PS1 mice it restored spatial learning and reduced brain inflammation in a 2021 study; in a rat model of Huntington's disease in 2024 it did not help.
?Can a US pharmacy compound dihexa?
No. Since its nomination was withdrawn in April 2026 it has been in no category of FDA's 503A list, so pharmacies cannot compound it. FDA's advisory committee is slated to review it by February 2027.
?Why is dihexa described as so potent?
Its reputation comes from its developers' papers on synapse formation, including the retracted 2014 paper. Comparisons of its potency with brain growth factors repeated online are not in the abstracts we hold and have not been independently replicated.
References
- [Animal] Sun X, et al. "AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway." Brain Sci, 2021;11(11). PMID: 34827486.
- [Animal] Weiss JB, et al. "Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies." Ann Med Surg (Lond), 2021;71:102917. PMID: 34703584.
- [pubmed] McCoy AT, et al. "Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents." J Pharmacol Exp Ther, 2013;344(1):141-54. PMID: 23055539.
- [pubmed] Wright JW, et al. "The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease." J Alzheimers Dis, 2015;45(4):985-1000. PMID: 25649658.
- [pubmed] Wright JW, et al. "The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases." Prog Neurobiol, 2015;125:26-46. PMID: 25455861.
- [pubmed] Wells RG, et al. "Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats." J Huntingtons Dis, 2024;13(1):55-66. PMID: 38489193.
Sources & Citations
Every citation on this page is PubMed-indexed and has been checked against its record. Four papers are listed without a card because they name dihexa only in their abstracts. A retracted 2014 paper is described in the text but not cited as support; its retraction status was read on PubMed on September 27, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.