Dihexa.
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide; also referenced as PNB-0408) is a small, orally active peptidomimetic derived from angiotensin IV (Ang IV), a C-terminal fragment of the renin-angiotensin system.
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide; also referenced as PNB-0408) is a small, orally active peptidomimetic derived from angiotensin IV (Ang IV), a C-terminal fragment of the renin-angiotensin system. Dihexa is research / preclinical, and PepCue grades its published evidence F tier (15/100). This is a research reference, not medical or dosing advice.
What it is
Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide; also referenced as PNB-0408) is a small, orally active peptidomimetic derived from angiotensin IV (Ang IV), a C-terminal fragment of the renin-angiotensin system. It was designed at Washington State University by chemically modifying Ang IV to increase lipophilicity and metabolic stability, yielding a brain-penetrant molecule investigated as a procognitive / antidementia research agent. It is a research chemical, not a drug; it has never been an approved medicine.
How it works
Dihexa was developed from Ang IV, whose procognitive effects were originally studied at the AT4/IRAP site, but its proposed primary mechanism is potentiation of hepatocyte growth factor (HGF) signaling through its receptor tyrosine kinase c-Met, which drives dendritic spine formation (spinogenesis) and synaptogenesis in hippocampal neurons. Activating HGF/c-Met is thought to remodel synaptic connectivity rather than act as a classical neurotransmitter. Important caveat: the central biochemical evidence that dihexa works by binding HGF and augmenting HGF/c-Met activation came from a paper that has since been retracted for data fabrication, so the molecular mechanism should be treated as unproven. The downstream behavioral phenotype (improved spatial learning in rodents) was reported in separate, non-retracted work.
Mechanism pathways
Raising growth factors that support neuronal survival, synapse formation, and plasticity.
Neurotrophic factors are proteins that keep neurons alive, guide the formation and strengthening of synapses, and support the structural changes underlying learning. The best-studied is brain-derived neurotrophic factor, which acts on the TrkB receptor tyrosine kinase to activate PI3K and Akt signalling for survival and MAPK signalling for growth, and which is required for long-term potentiation, the cellular process most closely associated with memory formation. Nerve growth factor acts similarly through TrkA. A separate system involves hepatocyte growth factor and its receptor tyrosine kinase c-Met, which in neurons is associated with dendritic spine formation and synaptogenesis. Compounds in this group approach the same idea from different angles. Several are short peptides derived from fragments of adrenocorticotropic hormone that lack the hormone's melanocortin-driven corticotropic activity, so they do not raise cortisol. Their best-characterised action in animal and cell studies is upregulation of BDNF and its TrkB receptor in the hippocampus and cortex, along with increased nerve growth factor expression, plus modulation of monoaminergic signalling and inhibition of enkephalin-degrading enzymes. One member of this subgroup is a chemically modified variant designed for greater stability, whose mechanism is inferred from the parent rather than independently established. Others are complex biological mixtures rather than single molecules, prepared from brain tissue, and their activity is attributed to many peptide interactions acting together. Proposed actions include mimicking endogenous neurotrophic factors, supporting neuronal energy metabolism, reducing excitotoxicity, and providing anti-apoptotic and antioxidant effects. Because the active components are not fully defined, batch consistency is an intrinsic issue with this format. A further compound is reported to raise BDNF transcription while inhibiting a cytokine signalling pathway, with downstream reduction of an enzyme implicated in abnormal tau phosphorylation. Another was developed to potentiate hepatocyte growth factor signalling at c-Met. Several honest caveats apply. Most of this evidence comes from rodent and cell-culture work. Some of the brain-derived mixtures are approved and widely used in certain countries while remaining unapproved and unavailable in others, and independent assessments of their clinical benefit have been mixed. For the c-Met compound, the central biochemical evidence for its proposed mechanism came from a publication that was retracted for data fabrication, and c-Met is a well-established oncology target, so chronic potentiation raises an unresolved risk question that no human study has addressed.
The evidence
There is NO human data on dihexa: no completed clinical trials, no published human pharmacokinetics or safety. The non-retracted foundational study (McCoy et al., J Pharmacol Exp Ther 2013, PMID 23055539) reported that orally administered dihexa reversed scopolamine-induced learning deficits and improved Morris water maze performance in aged (24-month) rats, and induced spinogenesis in cultured hippocampal neurons at picomolar concentrations. Later angiotensin-IV-analog work continued in disease models (e.g., a 2024 study of an Ang IV analog in a 3-nitropropionic-acid Huntington's-like rat model, PMID 38489193). Crucially, the most-cited mechanistic paper tying dihexa's cognitive effects to HGF/c-Met (Benoist et al., J Pharmacol Exp Ther 2014, PMID 25187433) was RETRACTED in 2025 (retraction notice PMID 40312093) after a Washington State University investigation found falsified/fabricated figure data; the widely repeated "thousands of times more potent than BDNF" claim derives from this now-discredited line of work and should not be cited as established fact. The honest summary: rodent behavioral evidence exists, but the headline mechanistic and potency claims rest partly on retracted literature, and human efficacy is entirely unestablished.
The evidence, in brief
A small, orally active angiotensin-IV-derived peptide that potentiates the HGF/c-Met system, promoting synaptogenesis in the hippocampus. All evidence is preclinical (rodent and cell models), with no completed human trials, and some foundational work in this area has faced scrutiny.
- The procognitive and synaptogenic effects of angiotensin-IV-derived peptides depend on HGF/c-Met activationJ Pharmacol Exp Ther, 2014 (PMID 25187433)
Evidence maturity
An evidence-only reading: approval status, human vs preclinical data, mechanism and safety. Popularity never raises it. Research file #016
Little indexed evidence or largely speculative.
A plausible biological rationale, but little data behind it.
Claim receipts
Popular claims about Dihexa, checked against the state of the evidence. The verdict describes evidence maturity, never an invented study result.
That figure derives from a mechanistic paper retracted in 2025 after an institutional investigation found falsified figure data, so it should not be repeated as established fact.
The central biochemical evidence for this mechanism was in the retracted paper, so the molecular mechanism should be treated as unproven even though separate non-retracted work reported behavioral effects.
Improved spatial learning in aged rats and spinogenesis in cultured hippocampal neurons come from non-retracted preclinical work; there is no human data of any kind.
No clinical trial has been completed, and no human pharmacokinetics or safety data have been published, so user reports carry the whole claim, on outcomes that are strongly placebo-responsive.
c-Met is a validated oncology target because aberrant HGF and c-Met signaling drives tumor proliferation and metastasis, so chronic potentiation raises an unresolved oncogenic question that no human study has addressed.
Safety profile
No human safety data exist; there is no published clinical adverse-event profile, and dihexa is sold only as a research chemical of variable purity. The principal theoretical concern follows directly from its proposed mechanism: c-Met is a validated oncology target because aberrant HGF/c-Met signaling promotes tumor proliferation, invasion, angiogenesis, and metastasis, so a chronic c-Met potentiator raises an unresolved oncogenic-risk question that no human study has addressed. Its reported long circulating half-life and high lipophilicity also mean tissue accumulation and off-target effects are poorly characterized. Because foundational mechanistic data were retracted for fabrication, even the basic biology underlying any risk assessment is uncertain.
Compound notes
- Dihexa is a peptide derived from angiotensin IV that potently activates the HGF/c-Met system.
- It is studied for synaptogenesis and cognition in animal models and is highly experimental.
- Not FDA-approved; early experimental research only.
- Potent growth-factor signaling raises theoretical risks; no human safety data.
Regulatory status
Dihexa is investigational/research-use-only: it is not approved by the FDA or any major regulator for any indication, has no DailyMed monograph, and has not completed human clinical trials. It is not a dietary supplement and is widely sold only as a "research chemical." It is not a WADA-listed named substance, though non-approved experimental compounds are broadly disallowed in sport.
Sold research-use-only; human evidence is limited or preclinical.
By the numbers
- 01Chemical identity: N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, an orally active angiotensin IV-derived peptidomimetic developed at Washington State University
- 02Proposed mechanism is potentiation of HGF/c-Met signaling to drive synaptogenesis, but the key biochemical evidence for this was retracted in 2025 for data fabrication
- 03No human trials, no human pharmacokinetic or safety data exist as of 2026
- 04Non-retracted rodent work (McCoy 2013, PMID 23055539) showed reversal of scopolamine deficits and improved water-maze performance in aged rats
- 05The popular 'orders of magnitude more potent than BDNF' claim traces to now-retracted/discredited literature
- 06Mechanistic overlap with the validated cancer target c-Met creates an unresolved theoretical oncogenic concern
Dihexa: research formats
Choose the format you are researching to see route-specific notes.
High lipophilicity gives this compound significant oral and transdermal bioavailability.
Dihexa is a highly lipophilic angiotensin analogue with unusually high CNS penetration due to its lipid solubility. Oral bioavailability is documented to be significant (unlike most peptides). Research use includes oral dissolved in DMSO or oil carrier, and sublingual or transdermal application has been explored.
Typical research concentrations for oral Dihexa are in the low-milligram range. The unusually high lipophilicity means it does not require the special diluent considerations of most water-soluble peptides.
Sources
Every factual claim above resolves to a real, published source.
- Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agentsJ Pharmacol Exp Ther, 2013, PMID 23055539 (foundational, non-retracted)
- Retraction notice: The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met systemJ Pharmacol Exp Ther, 2025 (retracts the 2014 mechanistic paper PMID 25187433), PMID 40312093
- The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseasesProg Neurobiol, 2015, PMID 25455861 (review)
- PubMed search: dihexa angiotensin IVPubMed live query for the full literature set
Cite this page
PepCue. “Dihexa: the evidence.” PepCue, reviewed June 1, 2026. https://www.pepcue.app/p/dihexa.
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