Section 01
What it's used for
Memory Study Under a Cloud
One rat study reported memory benefits in a maze test, including in aged rats, but a co-author was later found to have altered images in related papers. The journal issued a 2021 concern notice; two related papers were retracted in 2025.
▸Clinical wording
A single preclinical study reported that dihexa reversed scopolamine-induced spatial memory deficits in a Morris water maze test in rats and improved performance in aged, 24-month-old rats. That paper, however, carries a 2021 Notice of Concern after a misconduct investigation found image alterations by a co-author in related dihexa publications, and two companion papers from the same laboratory were formally retracted in 2025. No independent replication of these behavioral results by an outside laboratory was found, so the cognitive-enhancement claims for dihexa rest on a single, now-questioned animal study.
Alzheimer's Disease Research
Is being studied for its potential effect on synapses, the connections between brain cells. Research links synapse loss more closely to cognitive decline in Alzheimer's disease than any other single change measured.
▸Clinical wording
Targets synaptic loss — the strongest correlate of cognitive decline in AD.
Traumatic Brain Injury
Is being studied for traumatic brain injury. Researchers observed that it activates the HGF/c-Met signaling pathway, which in animal research is linked to helping repair nerve cells and restore connections between them after injury.
▸Clinical wording
HGF/c-Met signaling promotes neural repair and connectivity restoration.
Section 02
Mechanism of Action
A stabilised copy of a brain peptide
- Dihexa is a chemically stabilised derivative of a small brain peptide family.
- A review of 32 studies grouped it with analogues that improved memory tasks in rodent impairment models.
- That review noted these peptides act most reliably when delivered directly into the brain near learning.
- In transgenic mice, oral Dihexa raised brain levels of the parent peptide, so peripheral dosing changes brain chemistry.
▸Clinical wording
Angiotensin IV scaffold and brain exposure
Dihexa is a metabolically stabilised derivative of the angiotensin IV family. A systematic review of 32 experimental studies of brain renin-angiotensin peptides grouped Dihexa with Nle1-AngIV and LVV-hemorphin-7 among analogues that improved spatial working memory and passive avoidance in rodent models of cognitive impairment, while noting that these peptides act most reliably when delivered intracerebroventricularly close to the time of learning acquisition or retention testing (Ho and Nation, 2018). In APP/PS1 transgenic mice, orally administered Dihexa raised brain angiotensin IV measured by ELISA, indicating that peripheral dosing changes CNS tissue chemistry (Sun et al., 2021).
The strongest independent mouse dataset
- Alzheimer-model mice given oral Dihexa performed better in a water maze memory test.
- Their brain tissue showed more survival signalling and more of a synapse protein than untreated animals.
- Two inflammatory messengers fell and one anti-inflammatory messenger rose.
- Blocking that survival signal reversed the benefit, and the work came from an unconnected laboratory.
▸Clinical wording
PI3K/Akt signalling and synaptophysin in transgenic mice
The clearest independent mechanistic dataset comes from APP/PS1 mice given oral Dihexa. Treated animals improved in the Morris water maze; brain tissue showed increased PI3K and phosphorylated AKT, higher synaptophysin, lower IL-1beta and TNF-alpha and higher IL-10 than vehicle controls. Co-administration of the PI3K inhibitor wortmannin reversed the protective effects, which places PI3K/Akt upstream of the observed changes rather than merely alongside them. This work came from a group unconnected to the laboratory that originated the compound (Sun et al., 2021).
The headline mechanism has been retracted
- The usual explanation is that Dihexa binds a growth factor and amplifies its receptor signalling.
- That claim traces to two papers from the originating laboratory, both retracted in April 2025.
- A third oral memory study from that group still carries an unresolved Notice of Concern.
- Any account of Dihexa built on this mechanism therefore rests on withdrawn evidence.
▸Clinical wording
HGF/c-Met potentiation and its retracted evidence base
The mechanism usually quoted for Dihexa — binding hepatocyte growth factor and potentiating c-Met phosphorylation at subthreshold HGF concentrations — traces to two papers from the originating laboratory, both retracted in April 2025 after a 2021 Notice of Concern: Kawas et al. (2012), which reported the HGF binding and Met modification, and Benoist et al. (2014), which reported that the procognitive and synaptogenic effects depended on HGF/c-Met. The oral procognitive study of McCoy et al. (2013) still carries an unresolved Notice of Concern. Any HGF/c-Met account of Dihexa therefore rests on evidence that has been withdrawn.
One surviving experiment, in fish
- In zebrafish larvae Dihexa protected sensory hair cells against short exposure to two antibiotics.
- It did not protect against prolonged exposure to one of them.
- A growth factor blocker completely removed the protection, and three downstream signals were implicated.
- Two of its authors are the researchers responsible for the retracted work, so it corroborates rather than replicates.
▸Clinical wording
Partial HGF-dependent protection in zebrafish hair cells
One surviving experiment supports HGF involvement in a non-neuronal setting. In larval zebrafish, 1 microM Dihexa protected lateral-line hair cells against acute neomycin and gentamicin exposure across several drug concentrations, though it did not protect against chronic gentamicin. The HGF antagonist 6-AH completely attenuated the protection, and pharmacological data implicated Akt, TOR and MEK downstream. The paper carries no retraction or concern notice, but two of its authors are the researchers found responsible for the retracted work, so it corroborates rather than independently replicates (Uribe et al., 2015).
Rat results point in opposite directions
- In a rat sciatic nerve repair model Dihexa improved walking scores and reduced foot contractures.
- That study reported no mechanistic markers alongside the functional improvement.
- An independent group testing Dihexa against a nerve toxin in rats reported no protection at all.
- Weight, movement and spatial memory deficits were unchanged over five weeks in that study.
▸Clinical wording
Functional outcomes in rodent injury models are mixed
Two rodent studies with different endpoints diverge. In a rat sciatic nerve damage-repair model, Dihexa delivered to the gastrocnemius improved motor function on walking-track and footprint grading (P < 0.05) and reduced foot flexion contractures (P < 0.01) relative to vehicle, with no mechanistic markers reported (Weiss et al., 2021). In contrast, an independent group testing Dihexa (PNB-0408) against 3-nitropropionic acid neurotoxicity in male Wistar rats reported no protection: the weight, motor and spatial-memory deficits induced by 3-NP were unchanged over five weeks (Wells et al., 2024).
Section 03
Biological Pathways
- Angiotensin IV-derived brain exposureDihexa is a stabilised angiotensin IV analogue; a review grouped it with peptides that improved spatial working memory and passive avoidance in rodents, and oral dosing raised brain angiotensin IV in APP/PS1 mice.
- PI3K/Akt signalling in transgenic miceIn APP/PS1 mice, oral Dihexa improved Morris water maze performance and raised brain PI3K, phosphorylated AKT and synaptophysin while lowering IL-1beta and TNF-alpha; wortmannin reversed these effects.
- HGF/c-Met potentiation claimThe originating lab's account of Dihexa binding HGF and potentiating c-Met phosphorylation traces to two papers retracted in April 2025; a related procognitive study still carries an unresolved Notice of Concern.
- Mixed functional outcomes in rodent modelsIn zebrafish, Dihexa protected hair cells against ototoxins via a route blocked by the HGF antagonist 6-AH; in rats it improved sciatic nerve repair but gave no protection against 3-nitropropionic neurotoxicity.
Section 04
Dosage Information
N-hexanoic-Tyr-Ile-(6) aminohexanoic amide| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Oral — by tube in rats | Rats with drug-induced memory loss and 24-month-old rats | 1.25–2.0 mg/kg a day by tube and 0.05–0.50 mg/kg into the abdomen, same 2013 paper. It measured recovery, not gain in healthy rats | That paper has been flagged for image manipulation since 2021, two from the same lab were retracted in April 2025, and no human dose was derived. |
| Into a brain ventricle | Rat memory models, injected into the brain | 0.1–1 nmol straight into the brain — the amount that reaches nerve cells, with nothing lost to gut, liver or the brain's barrier | This route skips the barrier into the brain, so it sets no oral or skin dose. How much dihexa reaches a human brain has never been measured. |
| Subcutaneous — successor fosgonimeton | The only human dosing in this chemical lineage | Single doses of 2, 6, 20, 40, 60 and 90 mg in 88 phase 1 volunteers. The later phase 2/3 trial missed its main goal in September 2024 | A different molecule, made because dihexa could not be developed as a drug. Its milligrams say nothing about dihexa; its failure is the nearest human result. |
| Oral / on the skin — self-administration | Vendor copy and forum threads, no trial behind it | 5–20 mg a day by mouth or in DMSO on skin, some sources 20–30 mg — about 0.06–0.43 mg/kg at 70–90 kg, below the rat dose per kg | The "ten million times stronger than BDNF" line behind these amounts is a count of spines on cells in a dish, not a dose. Dihexa was never given to a person. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Storing the product
As a small molecule, dihexa is more stable than typical peptides and is stored as a powder at -20 °C. Good oral bioavailability is described for the substance, but no separate room-temperature shelf life is given for the powder.
After opening
For experimental use the powder is dissolved in DMSO or ethanol rather than reconstituted with water. It is active at nanomolar concentrations, so only a small amount is needed once dissolved; no post-dissolution storage window is specified.
Section 07
Side Effects & Precautions
Very limited safety data — primarily preclinical research. Theoretical concerns about c-Met pathway activation (c-Met is an oncogene), though no cancer promotion observed in animal studies at cognitive doses.
Section 08
Regulatory Status
It remains a research chemical: there is no approved label, indication, dose, or established human safety profile behind it.
FDA / United States
Not approved
In 2023 the FDA assigned dihexa to Category 2 of the interim 503A bulk-substances list and lifted that listing in April 2026 after the nomination was withdrawn; «dihexa acetate» is now scheduled for a fresh Pharmacy Compounding Advisory Committee hearing before the end of February 2027. Removal from Category 2 is not addition to the 503A Bulks List — dihexa is not on that list, so compounding pharmacies still have no lawful basis to prepare it for human use.
EU / EMA
Not approved
Dihexa has no EU marketing authorisation and does not appear among medicines under evaluation by the Committee for Medicinal Products for Human Use (CHMP); no manufacturer has filed for review in the European Union.
WADA
Prohibited under S0
Dihexa is not individually named on the Prohibited List, but as an unapproved pharmacological substance outside the growth-hormone/IGF-1 pathway covered by S2, it falls under the S0 catch-all for non-approved substances — banned at all times, in and out of competition, with no therapeutic-use exemption.
Clinical trials
No completed trial exists
Dihexa itself has never entered a registered human study; the related prodrug fosgonimeton (ATH-1017), whose active metabolite is dihexa, reached a Phase 2/3 Alzheimer's trial (LIFT-AD, NCT04488419) that missed its primary endpoint in September 2024.
A «research use only» label does not turn dihexa into an approved medicine and says nothing about its purity. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling PathwaySun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y. · Brain Sciences · 2021
- [2]Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposureUribe PM, Kawas LH, Harding JW, Coffin AB. · Frontiers in Cellular Neuroscience · 2015
- [3]Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair modelWeiss JB, Phillips CJ, Malin EW, Gorantla VS, Harding JW, Salgar SK. · Annals of Medicine and Surgery · 2021
- [4]Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in RatsWells RG, Azzam AF, Hiller AL, Sardinia MF. · Journal of Huntington's Disease · 2024
- [5]Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studiesHo JK, Nation DA. · Neuroscience and Biobehavioral Reviews · 2018
- [6]Retraction notice: The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System (Benoist et al., 2014)Journal of Pharmacology and Experimental Therapeutics editorial notice · Journal of Pharmacology and Experimental Therapeutics · 2025
- [7]Retraction notice: Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers (Kawas et al., 2012)Journal of Pharmacology and Experimental Therapeutics editorial notice · Journal of Pharmacology and Experimental Therapeutics · 2025
- [8]Notice of Concern: McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, and Harding JW (2013) Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia AgentsJournal of Pharmacology and Experimental Therapeutics editorial notice · Journal of Pharmacology and Experimental Therapeutics · 2021
Section 10
Frequently Asked Questions
The main evidence that dihexa improves memory is a single 2013 rat study reporting reversal of drug-induced memory loss and improved performance in aged rats. That paper has carried a Notice of Concern since 2021 after a misconduct investigation found image alterations by a co-author, and two related dihexa papers from the same laboratory were formally retracted in 2025. No outside laboratory has independently replicated the original results, and dihexa has never been tested in a human cognitive trial.
That figure describes a laboratory measurement, not a human dose or effect: it comes from counting new synaptic spines forming on cells in a dish exposed to dihexa versus BDNF, from the same body of work that is now partly retracted and under a Notice of Concern. It says nothing about how potent dihexa is at any dose taken by mouth or applied to skin, since that has never been measured in a person.
Self-administration figures — roughly 5 to 20 mg a day taken orally or dissolved in DMSO on skin — come entirely from vendor material and forum discussion, not from any human trial; dihexa has never been given to a person. The rat studies behind the compound used higher weight-adjusted doses (roughly 1.25-2 mg/kg by tube), and nobody has published a human dose derived from that animal data.
Dihexa is an investigational research compound with no FDA approval and no registered clinical trials in humans. It is not on the WADA prohibited list.
Dihexa itself has not — there is no record of it being given to a person. Its chemical successor, fosgonimeton, was tested in 88 people in a phase 1 trial across single doses from 2 to 90 mg, but that is a different molecule, developed specifically because dihexa could not be advanced as a drug; fosgonimeton's later phase 2/3 trial missed its main goal in September 2024, the nearest thing to a human result this chemical lineage has produced.
The two papers most often cited for how dihexa works — reporting that it binds hepatocyte growth factor and boosts c-Met receptor signalling — were both retracted in April 2025, following a 2021 Notice of Concern over image alterations in related dihexa publications from the same laboratory. A separately authored 2021 study in transgenic mice did find changes consistent with a PI3K/Akt signalling effect, so not all mechanistic evidence has been withdrawn, but the specific HGF/c-Met account has.
As a small molecule rather than a typical peptide, dihexa is described as more stable and is stored as a powder at -20°C; no separate room-temperature shelf life is given. For experimental use it is dissolved in DMSO or ethanol rather than water, and no storage window is specified for the dissolved solution.