Dihexa (research code PNB-0408) is a small, chemically modified peptide derived from angiotensin IV, a fragment of the hormone system that controls blood pressure. Researchers at Washington State University designed it in the early 2010s as a possible Alzheimer’s drug. In rats it was reported to cross into the brain, work by mouth and restore performance in memory tests (McCoy et al., JPET 2013).
Dihexa itself has never been tested in a registered human trial. The paper that established how it was supposed to work was retracted in 2025 after a university investigation found falsified or fabricated data (JPET retraction notice, 2025). The only human data come from fosgonimeton, an injectable “prodrug” that the body converts into the same molecule. Fosgonimeton failed its Phase 2/3 Alzheimer’s trial (Porsteinsson et al., J Alzheimers Dis Rep 2025).
This page summarizes what the animal studies, the fosgonimeton trials and regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Angiotensin IV analog; synthetic modified tripeptide |
| Other names | PNB-0408; ATH-1001; N-hexanoic-Tyr-Ile-(6) aminohexanoic amide |
| Formula / weight | C₂₇H₄₄N₄O₅, 504.7 g/mol (PubChem) |
| Proposed mechanism | Boosts signaling by hepatocyte growth factor (HGF) through its receptor MET; the key mechanism paper was retracted |
| Approval | Not approved for any medical use; FDA reports no human exposure data for dihexa acetate |
| Human data | Only as the active metabolite of fosgonimeton (ATH-1017), given by injection under the skin |
| Half-life | ≈12.7 days after IV dosing in rats (one study, 3 rats); ≈1.5 h in humans as the metabolite of fosgonimeton |
| US status | Not FDA-approved; not named in Schedule III; formerly in FDA’s compounding “category 2” (significant safety risks) |
| WADA | Not named; unapproved substances fall under S0, and S2.3 lists HGF and growth factor modulators |
What it is
Angiotensin IV is a six-amino-acid fragment of angiotensin II. Earlier animal work suggested that angiotensin IV and its analog norleucine¹-angiotensin IV (Nle¹-AngIV) improved memory. These peptides broke down within minutes and could not reach the brain, so they were not usable as drugs (McCoy et al., JPET 2013).
The Washington State group reported that Nle¹-AngIV’s activity sat in its first three amino acids. They then changed both ends of that core to make it stable and fat-soluble:
| Part of the molecule | Change |
|---|---|
| N-terminus | Hexanoic acid (a six-carbon fatty acid) attached in place of norleucine |
| Core | Tyrosine–isoleucine, kept from the parent peptide |
| C-terminus | 6-aminohexanoic amide added |
The result is N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, formula C₂₇H₄₄N₄O₅, molecular weight 504.7 g/mol (PubChem CID 129010512). The FDA’s substance registry lists “ATH-1001” as another name for dihexa (FDA GSRS, UNII 9WYX65A5C2).
Link to fosgonimeton
Fosgonimeton (ATH-1017) was developed by Athira Pharma. Its PubChem structure is dihexa with a phosphate group on the tyrosine ring (PubChem CID 156596375). In the Phase 1 trial, fosgonimeton was “rapidly converted” in plasma to its active metabolite ATH-1001 (Hua et al., J Alzheimers Dis 2022). Athira’s papers call this metabolite “fosgo-AM (previously ATH-1001)” and do not use the name dihexa (Johnston et al., Neurotherapeutics 2023). The fosgonimeton trials are therefore the closest thing to human data on dihexa.
Proposed mechanism
HGF is a growth factor that acts through the MET receptor, a tyrosine kinase found on neurons and many other cells. The developers proposed that dihexa binds HGF and helps it activate MET, which in turn grows new dendritic spines and synapses (the contact points between nerve cells).
The study that made this case (Benoist et al., JPET 2014) was retracted in 2025. The journal stated that Washington State University found falsified and/or fabricated data in figures 1B and 2A/C and in a later correction, and that Leen H. Kawas and Joseph W. Harding were “solely responsible” (retraction notice). A related 2012 paper on the same family of HGF-binding analogs was also retracted (retraction notice). The original 2013 dihexa paper has not been retracted but has carried an expression of concern since 2021 (JPET notice of concern).
Some independent work still points toward the HGF/MET system. Athira reported that fosgo-AM enhanced HGF/MET signaling in cell culture (Johnston et al., 2023). A separate lab found that MET antagonists blocked dihexa’s effects in injured rats (Martino et al., Neurotrauma Rep 2025).
Pharmacokinetics
The only published pharmacokinetic data on dihexa itself come from the 2013 rat paper, which is under an expression of concern (McCoy et al., 2013):
| Measure (rats) | Result |
|---|---|
| Stability in rat serum (test tube) | Half-life 335.5 min, vs 1.42 min for Nle¹-AngIV |
| Rat liver microsomes | Half-life 509.4 min; very low phase I metabolism |
| Terminal half-life, 10 mg/kg IV (n = 3) | 12.68 days |
| Terminal half-life, 20 mg/kg IP (n = 4) | 8.83 ± 2.41 days |
| Volume of distribution | 54.4 L/kg, suggesting wide distribution into tissues |
| Brain entry | Radiolabeled dihexa was concentrated in all brain regions compared with blood |
Human data look very different. After fosgonimeton injections, the active metabolite ATH-1001 peaked at about 0.5 h and was cleared with a half-life of about 1.5 h. A slower terminal phase of about 5 h was seen only occasionally, once levels had fallen to about 1% of peak. Exposure rose in proportion to dose, and the drug did not build up over 9 days (Hua et al., 2022).
No study has measured how much dihexa is absorbed by mouth in humans. The oral activity claim rests on rat studies and on computer predictions in the 2013 paper.
Regulatory status
- Not an approved drug. FDA states it “has not identified any human exposure data” on drug products containing dihexa acetate and lacks information on whether it would cause harm in humans (FDA).
- Compounding. Dihexa acetate was placed in FDA’s “category 2,” bulk substances that may present significant safety risks. FDA now lists it among category 2 substances whose nominations were withdrawn by the nominators.
- No registered trials under its own name. ClinicalTrials.gov returns no studies for “dihexa” or “PNB-0408.” The registered human trials use fosgonimeton (ATH-1017) (ClinicalTrials.gov).
- Controlled substances. Dihexa is not named in the DEA’s Schedule III list (21 CFR 1308.13).
- Sport. The WADA list does not name dihexa. Section S0 prohibits any substance without current approval for human therapeutic use. Section S2.3 names hepatocyte growth factor and “growth factor modulators” (WADA 2026 Prohibited List).
What the research shows
Animal studies of memory
All dihexa efficacy data are from animals. Several of the founding studies come from the lab later found responsible for falsified data, so they should be read with caution.
| Study | Model | Main reported result |
|---|---|---|
| McCoy et al., 2013 | Rats given scopolamine (a drug that impairs memory) | Dihexa by brain infusion, injection or mouth reversed water-maze deficits in a dose-dependent way; oral 2 mg/kg matched controls |
| McCoy et al., 2013 | 24-month-old rats, 6 per group | Daily oral dihexa improved water-maze learning on most test days |
| Sun et al., Brain Sci 2021 | APP/PS1 Alzheimer’s model mice, n = 12 per group | 1.44 or 2.88 mg/kg by gavage for 3 months improved water-maze performance, raised neuron counts and lowered inflammatory markers |
| Martino et al., 2025 | Rats after repeated mild brain injury | Dihexa infused into the brain ventricles dose-dependently restored working memory; MET antagonists blocked the effect |
| Wells et al., J Huntingtons Dis 2024 | 40 rats with a toxin-induced Huntington’s-like disease | No protection against weight, motor or memory deficits |
A 2018 systematic review of animal studies found that 8 of 9 studies in models of cognitive impairment reported benefits from angiotensin IV or its analogs, including dihexa. The review noted these peptides worked best when infused directly into the brain close to the time of learning (Ho & Nation, Neurosci Biobehav Rev 2018).
Nerve repair in animals
In a rat model of cut and surgically repaired sciatic nerves (6–8 rats per group), dihexa combined with stem cells and injected into the calf muscle improved walking-footprint scores at 8–16 weeks (Weiss et al., Ann Med Surg 2021). The benefit was reported for combinations, and the study was small.
Human trials of the prodrug fosgonimeton
Phase 1. This randomized, placebo-controlled trial enrolled 88 people, given once-daily injections under the skin: healthy young men (single doses of 2–90 mg), healthy older adults (20–80 mg for 9 days) and 11 people with Alzheimer’s (40 mg for 9 days). The authors reported the drug was safe and well tolerated at all doses. In the small Alzheimer’s group (7 on drug, 4 on placebo), a brain-wave timing measure (ERP P300 latency) moved toward normal (p = 0.027) (Hua et al., 2022).
LIFT-AD (Phase 2/3). This randomized, placebo-controlled trial tested daily fosgonimeton 40 mg for 26 weeks. The primary analysis included 287 people with mild-to-moderate Alzheimer’s who were not taking cholinesterase inhibitors (Porsteinsson et al., 2025):
| Endpoint at week 26 | Difference vs placebo (SE) | p |
|---|---|---|
| Global Statistical Test (primary) | −0.08 (0.10) | 0.70 |
| ADAS-Cog11 (cognition) | −0.70 (0.77) | 0.35 |
| ADCS-ADL23 (daily function) | +0.67 (0.92) | 0.61 |
The trial did not meet its primary or secondary endpoints. The open-label extension was terminated after LIFT-AD missed its primary endpoint (NCT04886063). A Phase 2 trial in Parkinson’s disease dementia and dementia with Lewy bodies (SHAPE) enrolled 28 people and ended early “due to study design limitations” (NCT04831281).
Side effects and risks
No human safety data on dihexa itself
There are no published human safety studies of dihexa as sold under that name. FDA states it lacks information on whether it would cause harm in people (FDA). Products sold online as “research chemicals” are not made under drug manufacturing standards. Their identity, purity and dose are not verified by any regulator.
What the fosgonimeton trial showed
LIFT-AD gives the best available picture of side effects from the molecule’s active form, though it used a different, injected drug product (Porsteinsson et al., 2025):
| Adverse event | Placebo (n = 218) | 40 mg (n = 224) | 70 mg (n = 107) |
|---|---|---|---|
| Any treatment-emergent adverse event | 60.6% | 78.1% | 87.9% |
| Injection site reactions | 14.2% | 57.1% | 72.9% |
| Eosinophilia (raised eosinophil white cells) | 0% | 7.1% | 7.5% |
| Pruritus (itching) | 1.8% | 4.5% | 5.6% |
| Stopped study drug due to adverse events | 4.1% | 10.7% | 21.5% |
Serious adverse events were 4.2% on fosgonimeton vs 6.9% on placebo, and there were no deaths. Randomization to 70 mg was stopped partway through, after Phase 2 data suggested similar efficacy to 40 mg with lower tolerability.
Theoretical cancer concern
MET is a well-known oncogene. When it is mutated or switched on persistently, it can drive tumor growth, survival and spread, and MET inhibitors are used as cancer drugs (Comoglio et al., Nat Rev Cancer 2018). A compound designed to boost HGF/MET signaling therefore raises a theoretical concern about promoting existing tumors. No study has tested this for dihexa, and the 26-week fosgonimeton trial was too short to assess cancer risk.
Long persistence in animals
If the rat half-life of about 12.7 days were to apply in people, repeated doses would accumulate over weeks. The human data on the metabolite show a much shorter half-life of about 1.5 h. The difference between the two has not been explained, and the rat figure comes from a paper under an expression of concern.
Key takeaways
- An angiotensin IV analog built for the brain. Dihexa is a modified tripeptide designed to be stable, oral and brain-penetrant, with effects in rats reported in 2013.
- The mechanism paper was retracted. A 2025 retraction cited falsified or fabricated data; the original dihexa paper carries an expression of concern.
- No human trials of dihexa itself. Human data come only from fosgonimeton, a phosphate prodrug that is converted to the same molecule (ATH-1001).
- The prodrug failed in Alzheimer’s. LIFT-AD showed no significant benefit on cognition or daily function at 26 weeks, and over half of treated participants had injection site reactions.
- Unapproved and unknown safety. FDA reports no human exposure data for dihexa acetate. Boosting MET, a known cancer driver, is a theoretical risk that has not been studied.
Sources
- McCoy AT, Benoist CC, Wright JW, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141–154. PubMed; PMC.
- 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 Agents, J Pharmacol Exp Ther, 344: 141-154; DOI: 10.1124/jpet.112.199497. J Pharmacol Exp Ther. 2021;378(3):313. PubMed.
- Benoist CC, Kawas LH, Zhu M, et al. 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;351(2):390–402. Retracted. PubMed.
- Benoist CC, Kawas LH, Zhu M, et al. 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;392(4):103567. PubMed.
- Kawas LH, McCoy AT, Yamamoto BJ, Wright JW, Harding JW. Retraction notice to “Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers” [J Pharmacol Exp Ther 340 (2012) 539-548]. J Pharmacol Exp Ther. 2025;392(4):103566. PubMed.
- National Center for Biotechnology Information. PubChem Compound Summary: dihexa (CID 129010512) and fosgonimeton (CID 156596375). PubChem; PubChem.
- U.S. Food and Drug Administration. Global Substance Registration System: Dihexa (UNII 9WYX65A5C2). FDA GSRS.
- Johnston JL, Reda SM, Setti SE, et al. Fosgonimeton, a novel positive modulator of the HGF/MET system, promotes neurotrophic and procognitive effects in models of dementia. Neurotherapeutics. 2023;20(2):431–451. PubMed.
- Hua X, Church K, Walker W, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the positive modulator of HGF/MET, fosgonimeton, in healthy volunteers and subjects with Alzheimer’s disease: randomized, placebo-controlled, double-blind, phase I clinical trial. J Alzheimers Dis. 2022;86(3):1399–1413. PubMed.
- Porsteinsson AP, Sabbagh M, Tariot PN, et al. Fosgonimeton in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis Rep. 2025;9:25424823251405817. PubMed; PMC.
- Martino KA, Nakhre A, Demarest RM, Devilbiss DM. Hepatocyte growth factor/MET activator rescues working memory deficits after repeated mild traumatic brain injury. Neurotrauma Rep. 2025;6(1):991–998. PubMed.
- Sun X, Deng Y, Fu 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):1487. PubMed.
- 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;13(1):55–66. PubMed.
- Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): a systematic review of experimental studies. Neurosci Biobehav Rev. 2018;92:209–225. PubMed.
- Weiss JB, Phillips CJ, Malin EW, 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. PubMed.
- Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018;18(6):341–358. PubMed.
- U.S. Food and Drug Administration. Certain bulk drug substances for use in compounding that may present significant safety risks. Content current as of April 22, 2026. FDA.
- ClinicalTrials.gov. Search for “dihexa” (no studies); records NCT04488419 (LIFT-AD), NCT04886063 (open-label extension, terminated) and NCT04831281 (SHAPE, terminated). ClinicalTrials.gov; NCT04886063; NCT04831281.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA 2026 Prohibited List.
- Code of Federal Regulations. Schedule III, 21 CFR 1308.13. 21 CFR 1308.13.