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Dihexa

Tier 3 · Reported use
Also known as PNB-0408 · N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide

All efficacy, mechanistic, and pharmacokinetic data for Dihexa itself comes from preclinical rodent, zebrafish, and in-vitro models — no completed or ongoing human clinical trials of Dihexa exist. The strongest human-level evidence in the source set is observational data on fosgonimeton (ATH-1017), a prodrug from the same drug class, which failed its Phase 3 Alzheimer's endpoint in 2024. Critically, two of the three foundational mechanism papers (Kawas et al. 2012 and Benoist et al. 2014) were retracted in April 2025 following a Washington State University investigation into falsified data/image manipulation, and the paper naming Dihexa (McCoy et al. 2013) carries a 2021 Expression of Concern. Independent replication (Sun et al. 2021, APP/PS1 mice) supports procognitive effects, but key mechanistic figures rest partly on discredited work.

Half-life
~304.8 h
Routes
Oral · Intravenous · Intraperitoneal · Intracerebroventricular · Subcutaneous · Topical/transdermal (vendor-reported)
Goals
Cognitive enhancement / nootropic · Neuroprotection · Neurorepair / recovery · Anti-neuroinflammation
Cost / mg
Not recorded

How it works

Dihexa is a synthetic, metabolically stabilized peptide derived from angiotensin IV. Rather than acting on classic receptors directly, it is reported to bind hepatocyte growth factor (HGF) and boost HGF's activity at its receptor, c-Met. Turning on this HGF/c-Met pathway is thought to trigger the growth of new connections between brain cells — promoting dendritic spines and functional synapses — which researchers link to improved learning and memory in animals. It is described as extraordinarily potent at building synapses in cultured neurons and is orally active and able to cross the blood-brain barrier in rodents. Importantly, all of this comes from animal and cell studies, and some of the original foundational papers have been retracted for data problems.

Overview

Overview

Dihexa (also known as PNB-0408; chemically N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a synthetic, metabolically stabilized angiotensin IV (AngIV) analog / peptidomimetic. It was developed by Joseph W. Harding, PhD, and John W. Wright, PhD, at Washington State University between roughly 2010 and 2014, first described in print in October 2012 (McCoy et al., 2013, Journal of Pharmacology and Experimental Therapeutics) and covered by US Patent 8598118.

  • Molecular formula: C27H44N4O5
  • Molecular weight: ~504.7 g/mol
  • CAS: 1401708-83-5

Dihexa is a first-in-class compound derived from the pre-prototype molecule Nle1-angiotensin IV, with its core procognitive activity residing in the three N-terminal amino acids Nle-Tyr-Ile. Benoist et al. (2011) described a C-terminally truncated Nle1-AngIV core sufficient to reverse scopolamine-induced spatial memory deficits in rats.

Proposed Mechanism

Dihexa is reported to bind hepatocyte growth factor (HGF) with high affinity and to allosterically potentiate the HGF/c-Met cascade — dimerizing with endogenous HGF to activate the c-Met (MET) receptor and downstream signaling. In vitro it induces c-Met phosphorylation in the presence of subthreshold HGF and augments HGF-dependent cell scattering. Activation of c-Met is proposed to stimulate mitogenesis, motogenesis, morphogenesis, neurogenesis, and neuroprotection, and to drive dendritic arborization, spinogenesis, and synaptogenesis.

In cultured hippocampal neurons, Dihexa promotes dendritic spine and functional synapse formation (measured as increased mEPSC frequency) at picomolar concentrations, and has been reported to be roughly seven orders of magnitude (~ten million-fold) more potent than BDNF — though this figure traces to a paper now under an Expression of Concern. Downstream signaling implicated includes PI3K/AKT, mTOR, and MEK.

Historically, AngIV's cognitive effects were attributed to the AT4 receptor, identified in 2001 as insulin-regulated aminopeptidase (IRAP), distributed in cognition-critical regions (hippocampal CA1–CA3, neocortex, thalamus, cerebellum). From ~2012 the Harding lab reframed the mechanism as direct HGF binding.

Preclinical Findings

  • Cognition: Oral Dihexa (2 mg/kg/day) improved Morris water maze performance in aged (24-month) rats and reversed scopolamine-induced deficits. In APP/PS1 Alzheimer's-model mice (Sun et al. 2021, an independent replication), it restored spatial learning and cognitive function. A 2018 systematic review of 32 AngIV-cognition studies found a consistent procognitive signal (8 of 9 studies with Dihexa/analogs positive), while emphasizing the evidence is entirely animal-based.
  • Neuropathology (APP/PS1 mice): increased neuronal density and synaptophysin, decreased astrocyte/microglia activation, reduced IL-1β and TNF-α, increased IL-10, and PI3K/AKT activation (reversed by wortmannin).
  • Other models: protected zebrafish lateral-line hair cells from ototoxins (neomycin/gentamicin at 1 μM); improved motor recovery when combined with mesenchymal stem cells in a rat sciatic nerve transection-repair model; used in vitro as an HGF agonist to differentiate hepatoblasts into hepatocyte-like cells.
  • Null/negative results: did not improve cognition in rats with normal cognition, and failed to protect rats in a 3-nitropropionic acid (3-NP) Huntington's-like model.

Pharmacokinetics

Dihexa is orally active and blood-brain barrier-permeable in rodents, with significant brain concentrations after systemic (including oral) dosing and oral cognitive effects comparable to subcutaneous injection. Reported ~38% oral absorption and resistance to amino-/carboxypeptidase degradation. Its circulating half-life is unusually long (~12.7 days IV, ~8.8 days IP in rats), versus ~2 minutes for native AngIV.

Investigational Uses

Dihexa is primarily investigated as an oral cognitive enhancer and potential treatment for Alzheimer's disease and other neurological disorders where augmented synaptic connectivity may be beneficial, with additional preclinical exploration in ototoxicity, nerve repair, and in-vitro hepatocyte differentiation. Fosgonimeton (ATH-1017), a prodrug derivative from the same drug class (Athira), entered Phase 2/3 Alzheimer's trials and failed its Phase 3 endpoint in September 2024.

Note on name collisions: Some sources referencing "diHexa" describe unrelated compounds — DOTA-diHexa alpha-MSH dimers for melanoma imaging, and DiOC6 (dihexa-oxacarbocyanine iodide), an ER-labeling dye. These are not the AngIV analog and should not be conflated.

What the research shows

235 findings extracted from the 30 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 1 human study finding, 37 animal findings, 6 in vitro findings, 13 expert opinion findings, 1 anecdotal finding and 2 theoretical findings.

  • human studyAthira's fosgonimeton (related to Dihexa's drug class) failed its Phase 3 Alzheimer's endpoint in 202424

  • animalDihexa exhibits excellent antidementia activity in scopolamine models2

  • animalDihexa exhibits excellent antidementia activity in aged rat models2

  • animalDihexa restored spatial learning and cognitive functions in the Morris water maze test in APP/PS1 mice3

  • animalDihexa exhibits excellent antidementia activity in scopolamine and aged rat models and marked synaptogenic activity3

  • animalDihexa restored spatial learning and cognitive functions in the Morris water maze test4

  • animalIn aged rats with induced cognitive deficits, Dihexa restored memory performance to levels comparable to healthy young animals through structural increases in dendritic spine density5

  • animalDihexa increases dendritic spine density by 40 to 60 percent in treated brain regions, with electrophysiology confirming these new spines form functional synaptic connections5

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  • animalAnimal studies showed dihexa reversed scopolamine-induced memory deficits in rodents and increased hippocampal synaptogenesis6

  • animalDihexa has demonstrated improvements in cognitive function in animal models of Alzheimer's disease-like impairment7

  • animalDihexa has produced potent improvements in cognitive performance in animal models of Alzheimer's disease-like impairment7

  • animalResearch published in Journal of Pharmacology and Experimental Therapeutics (McCoy et al., 2013) evaluated metabolically stabilized angiotensin IV analogs, including Dihexa, as pro-cognitive and anti-dementia agents, demonstrating meaningful cognitive improvements in animal models7

  • animalDihexa improves performance in rodent learning-and-memory models8

  • animalA 2018 systematic review confirmed a consistent procognitive signal across experimental studies in angiotensin-IV cognition literature, while underscoring that this body of work is animal-based8

  • animalChronic intracerebroventricular infusion of Nle1-AngIV via osmotic pump facilitated spatial learning acquisition in the Morris water maze9

  • animalNle1-AngIV could overcome scopolamine-induced memory deficits at picomolar doses9

  • animalOral dihexa (2 mg/kg/day) improved Morris water maze performance in 24-month-old rats10

  • animalDihexa reversed scopolamine-induced cognitive deficits10

  • animalDihexa restored spatial learning and memory in Morris water maze10

  • animalDihexa (PNB-0408) has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases11

  • animalPNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity11

  • animalDihexa restored spatial learning and cognitive functions in the Morris water maze test13

  • animalMotor function at 8-16 weeks post-nerve repair significantly improved with MSC + Dihexa administrations into gastrocnemius muscle14

  • animalMSC + Dihexa administration mitigated foot flexion contractures14

  • animalPeroneal nerve function recovered quickly with return of function at one week (∼2.0) in all groups combined14

  • animalSensory function in all nerve boundaries returned to nearly normal by 8 weeks (Grade 2.7 on a scale of Grade 0-3) in all groups combined14

  • animalIn models of cognitive deficit, dihexa improved performance on spatial working memory and passive avoidance tasks15

  • animalA Dihexa concentration of 1 μM confers optimal protection from acute treatment with neomycin or gentamicin in zebrafish larval lateral line hair cells17

  • animalDihexa has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD18

  • animalDihexa facilitates memory consolidation and retrieval18

  • animalDihexa improves cognition and increases synapses in rat models of cognitive dysfunction23

  • animalDihexa did not improve cognitive functions in rats with normal cognition23

  • animal8 of 9 studies found Ang IV and its analogs were effective in improving performance on spatial working memory and passive avoidance tasks23

  • animalSun et al. 2021 tested Dihexa in APP/PS1 transgenic mice (Alzheimer's disease model) and reported improved Morris water maze performance with reduced escape latency over training days24

  • animalBenoist et al. 2011 described a C-terminally truncated Nle1-AngIV core (Nle-Tyr-Ile) sufficient to reverse scopolamine-induced spatial memory deficits in rats26

  • animalAn independent 2021 study in APP/PS1 Alzheimer's-model mice replicated dihexa's procognitive effects through PI3K/AKT signaling27

  • animalPreclinical studies have suggested that dihexa may facilitate neurorepair processes following such injuries by promoting neuronal regeneration29

  • animalDihexa has demonstrated promising results in preclinical studies, indicating its potential as a novel therapeutic agent for various types of cancer29

  • in vitroDihexa shows cognitive enhancement at picomolar concentrations, making it approximately ten million times more potent than brain-derived neurotrophic factor in some synaptogenesis assays5

  • in vitroDihexa is approximately 10 million-fold more potent than brain-derived neurotrophic factor (BDNF) in spine induction in cultured neurons9

  • in vitroDOTA-diHexa(NC-NC)-amide binding activity was 1.75-fold higher than DOTA-NAPamide in vitro21

  • in vitrodiHexa(NC-NC)-Gly-Lys(DOTA)-amide binding activity was 3.37-fold higher than DOTA-NAPamide in vitro21

  • in vitroDOTA-diHexa(CN-NC)-amide binding activity was 2.34-fold higher than DOTA-NAPamide in vitro21

  • in vitroUsing human HBL melanoma cells, diHexa(NC-NC)-Gly-Lys(DOTA)-amide binding activity was sixfold higher than DOTA-NAPamide21

  • expert opinionDihexa remains an investigational molecule studied only in preclinical animal models and has not undergone human clinical trials for safety or efficacy6

  • expert opinionAll published evidence consists exclusively of preclinical research in rodent models—there are no peer-reviewed human studies demonstrating safety or efficacy6

  • expert opinionNo studies in humans have been published to date23

  • expert opinionNo studies have examined dihexa for age-related diseases23

  • expert opinionDihexa has been noted to be potentially the most promising for future testing in humans given the hydrophobicity, metabolic stability, blood-brain-barrier penetrance, and preclinical data showing cognitive benefits23

  • expert opinionThere are no published human clinical trials of Dihexa24

  • expert opinionKawas et al. 2012 established HGF-dimerization framing but was retracted in 202524

  • expert opinionBenoist et al. 2014 tied the procognitive effect to HGF/c-Met dependence but was retracted in 202524

  • expert opinionNo human trial has ever been completed for dihexa25

  • expert opinionNo completed or ongoing human efficacy trials appear in PubMed or ClinicalTrials.gov as of April 202625

  • expert opinionAll published cognition data comes from rodent and zebrafish models25

  • expert opinionThe related clinical-stage prodrug failed its pivotal Alzheimer's trial in September 202426

  • expert opinionNo human clinical trials have been completed27

  • anecdotalDihexa has been described in vendor catalogs and biohacker forums as a potent procognitive and synaptogenic agent, active at picomolar concentrations in rat hippocampal cultures26

  • theoreticalDihexa has zero published human clinical trials8

  • theoreticalDihexa may potentially slow down or even reverse cognitive decline29

How it works

Based on 45 animal findings, 20 in vitro findings, 11 expert opinion findings and 21 theoretical findings.

  • animalDihexa exhibits marked synaptogenic activity2

  • animalThe amount of AngIV in mouse tissue increased after administration of Dihexa compared to wild-type controls3

  • animalDihexa increased neuronal cells and expression of SYP (synaptophysin) protein in APP/PS1 mice3

  • animalDihexa decreased activation of astrocytes and microglia in APP/PS1 mice3

  • animalDihexa markedly reduced levels of pro-inflammatory cytokines IL-1β and TNF-α in APP/PS1 mice3

  • animalDihexa increased levels of anti-inflammatory cytokine IL-10 in APP/PS1 mice3

  • animalDihexa activated the PI3K/AKT signaling pathway in APP/PS1 mice3

  • animalPI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of Dihexa in APP/PS1 mice3

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  • animalThe amount of AngIV in mouse tissue increased after administration of Dihexa compared to wild-type group4

  • animalDihexa increased neuronal cells and expression of SYP protein in APP/PS1 mice4

  • animalDihexa decreased activation of astrocytes and microglia4

  • animalDihexa markedly reduced levels of pro-inflammatory cytokines IL-1β and TNF-α4

  • animalDihexa increased levels of anti-inflammatory cytokine IL-104

  • animalDihexa activated the PI3K/AKT signaling pathway4

  • animalPI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of Dihexa in APP/PS1 mice4

  • animalDihexa activates HGF/c-Met signaling in hippocampal and cortical regions at picomolar to nanomolar concentrations5

  • animalOne study in APP/PS1 transgenic mice (an Alzheimer's model) suggested dihexa reduced neuroinflammation and activated the PI3K/AKT signaling pathway6

  • animalDihexa has been found to be seven orders of magnitude more potent than brain-derived neurotrophic factor (BDNF) in assays of neurotrophic activity7

  • animalDihexa binds to HGF and potentiates its activity at the c-Met receptor on neurons, promoting formation of new synaptic connections7

  • animalThe synaptogenic effects of angiotensin-IV-derived peptides are dependent on activation of the hepatocyte growth factor (HGF) / c-Met system8

  • animalBlocking c-Met abolishes the synapse-building effect8

  • animalAT4 receptor is heavily distributed in brain regions critical for cognitive processing -- particularly the CA1-CA3 fields of the hippocampus, the neocortex, the thalamus, and the cerebellum9

  • animalIncreased neuronal cell density and SYP protein expression10

  • animalReduced activation of astrocytes and microglia10

  • animalDecreased IL-1beta and TNF-alpha; increased IL-1010

  • animalActivated PI3K/AKT signaling pathway; wortmannin reversed effects10

  • animalSmall-molecule-derived hepatocyte-like cells displayed typical functional characteristics as mature hepatocytes in vitro and repopulating injured liver in vivo12

  • animalThe amount of AngIV in mouse tissue increased after the administration of Dihexa compared to that in the WT group13

  • animalDihexa increased the neuronal cells and the expression of SYP protein in APP/PS1 mice in Nissl staining13

  • animalDihexa decreased the activation of astrocytes and microglia13

  • animalDihexa markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-1013

  • animalDihexa activated the PI3K/AKT signaling pathway13

  • animalPI3K inhibitor wortmannin significantly reversed the anti-inflammatory and anti-apoptotic effects of APP/PS1 mice13

  • animalDihexa shows beneficial effects through AT4R activation15

  • animalDihexa pretreatment does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating protection is mediated by intracellular events17

  • animalDihexa-mediated protection is attenuated by co-treatment with HGF antagonist 6-AH, indicating HGF activation is a component of the observed protection17

  • animalDihexa's protection is partially attenuated by co-treatment with inhibitors of downstream HGF targets Akt, TOR and MEK17

  • animalAddition of an amino group to the N-terminal of Dihexa attenuates the protective response17

  • animalDihexa induces dendritic arborization and synaptogenesis when stimulating the HGF/c-Met receptor system18

  • animalDespite higher affinity to MC1-R and excellent internalization in vitro, uptake by melanoma tumors in vivo was lower, possibly due to reduced tissue penetration21

  • animalDihexa activities have been linked to improved cognitive functions and increased dendritic arborization, spinogenesis, and synaptogenesis23

  • animalSun et al. 2021 reported increased synaptophysin (synaptic-density marker) in APP/PS1 mice treated with Dihexa24

  • animalSun et al. 2021 reported lower IL-1β and TNF-α in Dihexa-treated APP/PS1 mice, with effects attributed to PI3K/AKT signaling24

  • animalPreclinical cognitive restoration in scopolamine-treated and aged rodents has been reported25

  • animalEarly Ang IV analog Nle1-angiotensin IV reversed scopolamine-induced spatial memory deficits in rats through hippocampal AT4 receptors25

  • in vitroDihexa is seven orders of magnitude more potent than BDNF at building new connections between neurons in cultured hippocampal neurons8

  • in vitroDihexa and its angiotensin-IV-derived siblings promote the formation of new functional synapses in cultured hippocampal neurons8

  • in vitroDihexa promotes dendritic spine formation and synaptogenesis at picomolar concentrations in hippocampal neuron cultures9

  • in vitroInduced spinogenesis and synaptogenesis at picomolar concentrations in vitro10

  • in vitroCombining Vitamin C, Dihexa, and Forskolin (VDF) could substitute growth factors to induce hepatic specification12

  • in vitroDihexa is an analog of Ang IV15

  • in vitroDihexa is a hepatocyte growth factor agonist16

  • in vitroDihexa is a small molecule drug candidate that can allosterically activate the hepatocyte growth factor (HGF) cascade17

  • in vitroDihexa is chemically stable and blood-brain barrier permeable, unlike native HGF17

  • in vitroDihexa acts as a synthetic HGF mimetic by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades17

  • in vitroBoth melanotic and amelanotic melanomas (over-)express the melanocortin-1 receptor (MC1-R), the target for alpha-MSH21

  • in vitroDimerized MSH analogs display increased receptor affinity compared to monomeric MSH21

  • in vitroUptake by cultured B16-F1 cells was rapid and almost quantitative21

  • in vitroDiOC6 (dihexa-oxacarbocyanine iodide) is an agent that labels the endoplasmic reticulum (ER)22

  • in vitroFRET spectra indicated energy transfer between DiOC6 and CPO but no significant transfer between NAO and CPO22

  • in vitroCPO and DiOC6 show similar pattern of subcellular localization22

  • in vitroCPO relocalization can occur during irradiation22

  • in vitroCPO-catalyzed photodamage to both ER and mitochondrial Bcl-222

  • in vitroDihexa binds with high affinity to the hepatocyte growth factor (HGF) and promotes mesenchymal-epithelial transition factor (c-Met) signaling23

  • in vitroMcCoy et al. 2013 claim Dihexa is seven orders of magnitude more potent than BDNF at building synapses, based on in-vitro dendritic-spine assay24

  • expert opinionTwo of the three foundational mechanism papers were formally retracted in April 202526

  • expert opinionDihexa's chemical name is N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide, and its molecular formula is C₂₇H₄₄N₄O₅26

  • expert opinionThe original mechanism model attributed AngIV's effects on memory and cognition to activity at a binding site labeled the AT4 receptor, identified in 2001 by Albiston and colleagues as insulin-regulated aminopeptidase (IRAP)26

  • expert opinionBeginning around 2012, the Harding lab proposed that AT4-family analogs bind directly to hepatocyte growth factor (HGF), modulating its dimerization and altering signaling through its receptor tyrosine kinase c-Met (MET)26

  • expert opinionDihexa (developmental code PNB-0408) is a six-amino-acid angiotensin IV analog engineered to be orally active and to cross the blood-brain barrier27

  • expert opinionProposed mechanism is potentiation of hepatocyte growth factor (HGF) signaling at the c-Met receptor, driving synaptogenesis and spinogenesis at picomolar concentrations in vitro27

  • expert opinionDihexa binds with high affinity to HGF and potentiates its activity at c-Met receptor27

  • expert opinionDihexa and Nle1-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself27

  • expert opinionNew dendritic spines form functional synapses measured electrophysiologically as increased miniature excitatory postsynaptic current frequencies27

  • expert opinionActivation of PI3K/AKT signaling supports neuronal survival and reduce apoptosis27

  • expert opinionDihexa is a neuroactive peptide that enhances brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity28

  • theoreticalDihexa potentiates hepatocyte growth factor at the c-Met receptor, promoting formation of new synapses5

  • theoreticalDihexa works through potentiating hepatocyte growth factor at the c-Met receptor, a pathway involved in synapse formation5

  • theoreticalDihexa is a peptidomimetic with small molecular weight (~504 Da) designed to mimic peptide binding activity while resisting enzymatic degradation5

  • theoreticalThe compound was developed as a metabolically stabilized angiotensin IV analog designed to cross the blood-brain barrier and theoretically enhance synaptic connectivity6

  • theoreticalPreclinical research suggests dihexa may activate the hepatocyte growth factor (HGF)/c-Met receptor system, which theoretically could stimulate synaptogenesis and dendritic arborization6

  • theoreticalDihexa is an oligopeptide drug derived from angiotensin IV that binds with high affinity to hepatocyte growth factor (HGF) and potentiates its activity at the c-Met receptor7

  • theoreticalDihexa is chemically N-hexanoic-Tyr-Ile-(6) aminohexanoic amide and is engineered from angiotensin IV8

  • theoreticalDihexa was designed with structural modifications that confer enzymatic stability, blood-brain barrier (BBB) permeability, and oral bioavailability9

  • theoreticalDihexa acts through allosteric potentiation of HGF at the c-Met receptor tyrosine kinase and promotes synaptogenesis via PI3K/AKT/mTOR signaling9

  • theoreticalDihexa is an angiotensin IV analog11

  • theoreticalActivation of the c-Met receptor stimulates mitogenesis, motogenesis, morphogenesis, the ability to mediate stem cell differentiation and neurogenesis, and protects against tissue insults in a wide range of cells including neurons18

  • theoreticalDihexa is a first-in-class compound derived from the pre-prototype molecule Nle1-angiotensin IV18

  • theoreticalDihexa is a small molecule AngIV-based compound that is metabolically stable and penetrates the blood-brain barrier19

  • theoreticalThe brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system19

  • theoreticalAngIV interacts with the AT4 receptor subtype, with links to the insulin-regulated aminopeptidase (IRAP)19

  • theoreticalActivation of the c-Met receptor can stimulate neurogenesis and protect against tissue insults in many types of cells including neurons23

  • theoreticalThe proposed mechanism is that Dihexa potentiates hepatocyte growth factor (HGF) signaling at the c-Met (MET) receptor, downstream of PI3K-AKT, driving dendritic spine formation and synaptogenesis24

  • theoreticalDihexa is structurally an oligopeptide, allowing it to effectively cross the blood-brain barrier29

  • theoreticalDihexa therapy's mechanism of action involves the potentiation of hepatocyte growth factor (HGF) and its receptor, c-Met, which plays a crucial role in synaptic plasticity and neurotrophic support29

  • theoreticalDihexa binds itself with an enzyme called hepatocyte growth factor (HGF) associated with the generation of fresh neurons29

  • theoreticalResearch indicates that dihexa fosters the development of novel neurons and reinforces synaptic connections within the brain29

Dosing

Based on 2 animal findings and 1 theoretical finding.

  • animalThe estimated oral dose range from animal research is approximately 1–8 mg/kg5

  • animalBrain RAS peptides including dihexa appear most effective administered intracerebroventricularly15

  • theoreticalDihexa is available in capsule (oral delivery) and topical (transdermal application) formats7

How the body handles it

Based on 22 animal findings, 1 in vitro finding, 1 expert opinion finding and 3 theoretical findings.

  • animalDihexa has a long cyclic half-life2

  • animalDihexa can be orally administered and cross the blood-brain barrier (BBB) in APP/PS1 mice3

  • animalDihexa can be orally administered and cross the blood-brain barrier in APP/PS1 mice4

  • animalDihexa is orally bioavailable in animal models, with cognitive effects comparable to subcutaneous injection5

  • animalPreclinical studies document significant brain concentrations after systemic including oral administration5

  • animalDihexa is orally active and blood-brain barrier permeable7

  • animalDihexa is orally bioavailable and capable of crossing the blood-brain barrier7

  • animalDihexa has an extraordinarily long serum half-life of approximately 12.7 days following intravenous administration in rats9

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  • animalCompound demonstrated oral bioavailability and BBB permeability10

  • animalMetabolic stability: Resistance to aminopeptidase and carboxypeptidase degradation10

  • animalApproximately 38% oral absorption10

  • animalDihexa can be orally administered and cross the BBB in APP/PS1 mice13

  • animalDihexa is orally active18

  • animalDihexa penetrates the blood-brain barrier18

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.11 for [(111)In]DOTA-diHexa(NC-NC)-amide21

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.26 for diHexa(NC-NC)-Gly-Lys([(111)In]DOTA)-amide21

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.36 for [(111)In]DOTA-diHexa(CN-NC)-amide21

  • animalTumor-to-kidney ratios 4 hr postinjection were 1.67 for [(111)In]DOTA-NAPamide21

  • animalDihexa crosses the blood-brain barrier based on rodent studies23

  • animalDihexa shows oral bioavailability and blood-brain barrier penetration in rodent studies25

  • animalDihexa demonstrated a circulating half-life of 12.68 days after intravenous administration and 8.83 days after intraperitoneal administration in Sprague-Dawley rat studies27

  • animalDihexa demonstrated a prolonged circulating half-life (t1/2) of 12.68 days subsequent to i.v. administration and 8.83 days following i.p. administration in adult male Sprague-Dawley rats29

  • in vitroAngiotensin IV is a hexapeptide fragment (Val-Tyr-Ile-His-Pro-Phe) of angiotensin II with a serum half-life of roughly two minutes9

  • expert opinionDihexa is an oral active, blood-brain barrier-permeable angiotensin IV analogue with a long cyclic half-life3

  • theoreticalDihexa's small molecular weight and non-peptide backbone make it unrecognizable to aminopeptidases and carboxypeptidases5

  • theoreticalDihexa was designed to be metabolically stable and orally active while keeping procognitive activity8

  • theoreticalBoth N-terminus hexanoic-acid acyl group and C-terminus 6-aminohexanamide chain modifications protect against exopeptidase digestion and dramatically increase lipid solubility, allowing Dihexa to cross the blood-brain barrier in rodent studies after oral dosing26

Safety and side effects

Based on 1 animal finding, 19 expert opinion findings and 3 theoretical findings.

  • animalRadiolabeled alpha-MSH dimer peptides show marked increase of kidney uptake, explaining unfavorable in vivo ratios21

  • expert opinionNo human trials of any kind have been published, and long-term safety is entirely unknown5

  • expert opinionDihexa is an experimental compound that has never been approved by the FDA or any regulatory agency for the treatment of cognitive impairment, Alzheimer's disease, or any other neurodegenerative condition6

  • expert opinionDihexa has no established safety profile in humans, no known therapeutic dosing range, and no data on potential adverse effects in patients6

  • expert opinionLong-term human safety data are not yet established; current body of research on Dihexa is primarily preclinical7

  • expert opinionDihexa is prohibited under WADA S0 (Non-Approved Substances)9

  • expert opinionNo studies in animals or humans have examined the long-term safety of dihexa23

  • expert opinionDihexa's foundational mechanism papers were retracted in 2025 after a WSU investigation found image manipulation by the lead author24

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  • expert opinionMcCoy et al. 2013 carries a 2021 Expression of Concern24

  • expert opinionFoundational biochemistry papers for dihexa were retracted in April 202525

  • expert opinion69% of nootropic samples in a 2025 market surveillance study sourced from gray-market channels failed quality or labeling standards25

  • expert opinionDihexa is not FDA-approved for any human indication as of April 202625

  • expert opinionDihexa has no IND, NDA, or FDA drug classification25

  • expert opinionDihexa is distributed as a research use only chemical through gray-market and online research-chemical vendors25

  • expert opinionDihexa has never entered human clinical trials26

  • expert opinionThe proposed c-Met receptor mechanism overlaps with a recognized cancer pathway26

  • expert opinionThe McCoy 2013 paper that introduces Dihexa by name carries an Expression of Concern issued in September 202126

  • expert opinionThe 2014 Benoist paper that established the Kd = 65 pM HGF binding figure was retracted in April 2025 after a Washington State University investigation found falsified data27

  • expert opinionLong-term safety, particularly around chronic activation of a pathway involved in tumor biology, is entirely unstudied27

  • expert opinionThe 2013 McCoy paper carries a Notice of Concern27

  • theoreticalDihexa has no approved indication anywhere, no human efficacy data, no established human dose, and no long-term safety profile8

  • theoreticalDihexa via activation of HGF and c-Met could theoretically promote tumorigenesis and cancer progression23

  • theoreticalDihexa has a long half-life and there are theoretical concerns of c-Met activation leading to tumorigenesis and cancer progression23

What people use it for

Based on 5 animal findings, 3 in vitro findings, 2 expert opinion findings and 5 theoretical findings.

  • animalPNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model11

  • animalDihexa administration can improve recovery of limb function following peripheral nerve damage in rat sciatic nerve transection-repair model14

  • animalDihexa is a promising candidate for adjunct therapy to promote limb functional recovery after surgical nerve repair14

  • animalDihexa is most effective close to the time of learning acquisition or retention testing15

  • animalDihexa holds clinical potential for mitigating chemical ototoxicity17

  • in vitroDihexa as part of VDF cocktail enabled hepatoblasts to expand and mature into functional hepatocyte-like cells12

  • in vitroDihexa is used to differentiate hepatoblasts to hepatocyte-like cells in vitro from human pluripotent stem cells16

  • in vitroDimeric analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) labeled with radiometals are potential candidates for diagnosis and therapy of melanoma by receptor-mediated tumor targeting21

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  • expert opinionDihexa was developed at Washington State University as a potential oral cognitive enhancer targeting the HGF/c-Met pathway25

  • expert opinionDihexa (PNB-0408) is a small angiotensin IV–derived oligopeptide developed in a Washington State University laboratory between 2010 and 201426

  • theoreticalDihexa may be efficacious as a treatment for Alzheimer's disease18

  • theoreticalDihexa shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses19

  • theoreticalDihexa is primarily being investigated for its potential applications in augmenting cognitive function and addressing neurological disorders29

  • theoreticalDihexa is also being explored for its benefits in neurological conditions such as stroke and traumatic brain injury (TBI)29

  • theoreticalDihexa is currently being investigated for its ability to inhibit the growth and spread of cancer cells29

Other findings

Based on 7 expert opinion findings and 3 theoretical findings.

  • expert opinionDihexa is a synthetic, metabolically stabilized analog of angiotensin IV developed by Joseph W. Harding, PhD, and John W. Wright, PhD, at Washington State University9

  • expert opinionNo human clinical trials have been completed for dihexa itself9

  • expert opinionFosgonimeton (ATH-1017), a prodrug derivative of dihexa, entered Phase 2/3 clinical trials for Alzheimer disease9

  • expert opinionNo human clinical trials for safety, pharmacokinetics, or efficacy10

  • expert opinionDihexa is a synthetic oligopeptide derived from angiotensin IV, developed in the Harding and Wright labs at Washington State University24

  • expert opinionDihexa is a peptidomimetic derived from angiotensin IV25

  • expert opinionDihexa was first described in print in October 2012 in The Journal of Pharmacology and Experimental Therapeutics by graduate student Alene McCoy26

  • theoreticalDihexa is a modified hexanoic acid-Tyr-Ile dipeptide derived from angiotensin IV5

Show the remaining 2

  • theoreticalFull chemical name is N-(1-Oxohexyl)-l-tyrosyl-N-(6-amino-6-oxohexyl)-l-isoleucinamide, with molecular formula C27H44N4O5 and molar mass 504.672 g/mol27

  • theoreticalDihexa (also known as PNB-0408, or scientifically as N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a derivative of angiotensin IV, which is part of the renin-angiotensin system29

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

Foundational mechanism papers were retracted for data falsification.

Multiple sources report that two of the three foundational Dihexa mechanism papers (Kawas et al. 2012 and Benoist et al. 2014) were retracted in April 2025 after a WSU investigation found falsified data/image manipulation, and the paper naming Dihexa (McCoy et al. 2013) carries a 2021 Expression of Concern. The retracted Benoist 2014 paper established the widely cited Kd = 65 pM HGF binding figure and the HGF/c-Met dependence, so key mechanistic claims rest partly on now-discredited work. Independent work (Sun et al. 2021, APP/PS1 mice) is cited as replicating procognitive effects.

Limited evidence

No human data exists; all efficacy evidence is preclinical.

Every source that addresses it states no human clinical trials of Dihexa have been completed or are ongoing; all cognition, safety, and pharmacokinetic data come from rodent and zebrafish models. There is no established human dose, no human safety profile, and no FDA approval or drug classification.

Contested

Negative and null results temper the broad procognitive narrative.

While most sources emphasize procognitive benefit in impaired animals, Dihexa notes Dihexa did not improve cognition in rats with normal cognition, and Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats. reports PNB-0408 failed to protect rats in a 3-NP Huntington's-like model. Additionally, the related prodrug fosgonimeton failed its Phase 3 Alzheimer's endpoint in 2024, indicating the drug class did not translate to human efficacy.

Other

Some 'diHexa' sources describe entirely different compounds (name collision).

Dimeric DOTA-alpha-melanocyte-stimulating hormone analogs: synthesis and in vivo characteristics of radiopeptides with high in vitro activity. concerns DOTA-diHexa alpha-MSH dimer analogs for melanoma imaging, and Studies on the subcellular localization of the porphycene CPO. concerns DiOC6 (dihexa-oxacarbocyanine iodide), an ER-labeling dye — these are unrelated to the angiotensin IV analog Dihexa (PNB-0408) and should not be conflated with its properties.

Limited evidence

Theoretical cancer risk from c-Met activation is unstudied in Dihexa users.

Several sources raise a theoretical concern that Dihexa's activation of the HGF/c-Met pathway — a recognized cancer pathway — combined with its very long half-life could promote tumorigenesis, but this is explicitly theoretical and no long-term safety studies in animals or humans have examined it.

Single source

Specific potency and spine-density figures come from limited or vendor sources.

The ~40–60% dendritic spine density increase (Dihexa: HGF/c-Met Mechanism, Potency & Human Trial Status) and ~38% oral absorption (Dihexa Research Studies and Evidence | Peptide Protocol Wiki) appear in single sources, and the widely repeated 'ten million-fold more potent than BDNF' figure traces to the McCoy 2013 paper now under an Expression of Concern.

Single source

The widely repeated ~12.7-day half-life of Dihexa comes from a single rat study and is extraordinarily long for such a small molecule.

The figure of roughly 12.7 days after intravenous dosing (and about 8.8 days after intraperitoneal dosing) in Sprague-Dawley rats traces to one 2013 pharmacokinetic experiment by the original Washington State University group, using radiolabeled ([3H]) drug — the same foundational paper that now carries a 2021 Expression of Concern. A multi-day circulating half-life is highly unusual for a ~505-dalton peptide analog; native angiotensin IV clears in roughly two minutes, and radiolabel-based measurements can reflect retained label or breakdown products rather than intact circulating drug. No independent study has reproduced the value and no human pharmacokinetic data exist, so it should be treated as a single unconfirmed estimate rather than an established property — a point that matters because the long half-life is often cited as amplifying the theoretical cancer concern tied to c-Met activation.

Single source

The single strongest peer-reviewed study showing that Dihexa binds HGF and works through the c-Met receptor has been retracted.

The 2014 paper in the Journal of Pharmacology and Experimental Therapeutics (Benoist and colleagues) provided the direct biochemical evidence for Dihexa's mechanism — high-affinity HGF binding, c-Met activation in the presence of low HGF, and loss of the memory effect when c-Met is blocked. It was retracted in April 2025 after a Washington State University investigation found image manipulation. This is the same study usually cited as the highest-quality primary evidence for how Dihexa works, so the confident mechanistic picture rests substantially on discredited work; the main surviving independent support is indirect, from a 2021 mouse study showing PI3K/AKT activation.

Single source

The widely repeated claim that Dihexa lingers in the body for nearly two weeks rests on a single rat study whose source paper carries an Expression of Concern.

The ~12.7-day intravenous half-life (and ~8.8-day intraperitoneal) figure comes from one radiolabeled pharmacokinetic experiment in Sprague-Dawley rats reported in the 2013 McCoy paper, which now carries a 2021 Expression of Concern. A circulating half-life of nearly two weeks is highly unusual for a peptide-like molecule of only ~505 daltons — for comparison, native angiotensin IV clears in roughly two minutes — and the value has not been independently reproduced or measured in humans. It should be treated as a single unverified preclinical measurement rather than an established property.

Safety and side effects

Safety & Caveats

No human safety profile exists. No studies in animals or humans have examined the long-term safety of Dihexa. There is no established human therapeutic dosing range and no data on adverse effects in people. All cognition, safety, and pharmacokinetic data derive from rodent and zebrafish preclinical models — no human clinical trials have been completed or are ongoing.

Theoretical cancer risk

Because Dihexa activates the HGF/c-Met pathway — a recognized cancer pathway — it could theoretically promote tumorigenesis and cancer progression. This concern is heightened by its very long circulating half-life (~12.7 days IV in rats). This risk is explicitly theoretical and unstudied in Dihexa users; no long-term safety studies address it.

Integrity of the evidence base

  • Two of the three foundational mechanism papers — Kawas et al. 2012 and Benoist et al. 2014 — were retracted in April 2025 after a Washington State University investigation found falsified data / image manipulation. The retracted Benoist 2014 paper established the widely cited Kd = 65 pM HGF binding figure and the HGF/c-Met dependence.
  • The McCoy et al. 2013 paper that introduces Dihexa by name carries an Expression of Concern (issued September 2021) — the source of the "ten million-fold more potent than BDNF" figure.
  • The related prodrug fosgonimeton failed its Phase 3 Alzheimer's endpoint (2024), indicating the drug class did not translate to human efficacy.

Regulatory / quality status

  • Dihexa is not FDA-approved for any human indication (as of April 2026), has no IND, NDA, or FDA drug classification, and is distributed as a research-use-only chemical through gray-market and online research-chemical vendors.
  • It is prohibited under WADA category S0 (Non-Approved Substances).
  • A 2025 market surveillance study reported that 69% of nootropic samples from gray-market channels failed quality or labeling standards, raising concerns about product identity and purity.

Efficacy caveats

Dihexa did not improve cognition in normal (unimpaired) rats and failed to protect against 3-NP toxicity in a Huntington's-like model — the procognitive signal is largely confined to impaired-animal models.

Reconstitution and handling

Preparation & Dosing

No dose has been established for this compound. No regulatory label exists for it, so the figures below are what sources report — not guidance.

Important: Dihexa has no established human dose, no approved formulation, and no human safety data. The information below summarizes preclinical (animal) dosing and vendor-described formats only; it is not guidance for human use.

Formats (vendor-reported)

Vendor materials describe Dihexa as available in capsule (oral) and topical (transdermal) formats. Unlike many research peptides, Dihexa is notably orally active and blood-brain barrier-permeable in rodents, with oral cognitive effects reported comparable to subcutaneous injection and roughly 38% oral absorption in preclinical studies.

Preclinical dosing (rats)

Reported research doses include:

  • Oral: 2 mg/kg (with an estimated effective range of ~1–8 mg/kg across studies; 2–4 mg/kg used in a nerve-repair study)
  • Intracerebroventricular (i.c.v.): up to 1 nmol
  • Intravenous (i.v.): up to 10 mg/kg
  • Intraperitoneal (i.p.): up to 20 mg/kg

Oral 2 mg/kg/day was the dose used in aged-rat and scopolamine-deficit cognition studies. Brain renin-angiotensin system peptides, including Dihexa, appear most effective when administered i.c.v. and close to the time of learning acquisition or retention testing in these models.

Stability note

Dihexa's N-terminal (N-hexanoic acyl) and C-terminal (6-aminohexanamide) modifications increase hydrophobicity, decrease hydrogen bonding, and protect against exopeptidase digestion, giving it markedly greater metabolic stability than native angiotensin IV (whose serum half-life is only ~2 minutes) and an unusually long circulating half-life (~12.7 days IV in rats).

Sources

Ordered by evidence quality — the strongest first.

  1. The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2014Retracted

    PubMed lists this paper as a Retracted Publication (PMID 25187433). Findings citing it are kept for the record and marked where they appear.

  2. (PDF) AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers ...(opens in a new tab)
    Tier 2Web · researchgate.net
  3. AngIV-Analog Dihexa Rescues Cognitive Impairment and ...(opens in a new tab)
    Tier 2Web · pmc.ncbi.nlm.nih.gov
  4. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway(opens in a new tab)
    Tier 2Web · pmc.ncbi.nlm.nih.gov
  5. Dihexa: HGF/c-Met Mechanism, Potency & Human Trial Status(opens in a new tab)
    Tier 2Web · peptpedia.org
  6. Is Dihexa an approved and safe treatment for cognitive impairment or neurodegenerative diseases such as Alzheimer disease?(opens in a new tab)
    Tier 2Web · droracle.ai
  7. What is Dihexa? Benefits, mechanism, and uses for cognitive function - Cenegenics(opens in a new tab)
    Tier 2Web · cenegenics.com
  8. Dihexa: a striking preclinical nootropic with zero human evidence | Aminoscope(opens in a new tab)
    Tier 2Web · aminoscope.com · 2026
  9. Dihexa: Research Evidence & Safety Profile | PeptideInsight(opens in a new tab)
    Tier 2Web · peptideinsight.com · 2026
  10. Dihexa Research Studies and Evidence | Peptide Protocol Wiki(opens in a new tab)
    Tier 2Web · peptideprotocolwiki.com · 2026
  11. Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  12. Efficiently generate functional hepatic cells from human pluripotent stem cells by complete small-molecule strategy.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  13. AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  14. 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.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  15. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  16. Small-Molecule-Directed Hepatocyte-Like Cell Differentiation of Human Pluripotent Stem Cells.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2016
  17. Hepatocyte growth factor mimetic protects lateral line hair cells from aminoglycoside exposure.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2015
  18. The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2015
  19. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2015
  20. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2013Expression of concern

    PubMed carries an expression of concern about this paper (PMID 23055539). Findings citing it are kept for the record and marked where they appear.

  21. Dimeric DOTA-alpha-melanocyte-stimulating hormone analogs: synthesis and in vivo characteristics of radiopeptides with high in vitro activity.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2007
  22. Studies on the subcellular localization of the porphycene CPO.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2005
  23. Dihexa(opens in a new tab)
    Tier 3Web · alzdiscovery.org
  24. Dihexa for Memory: What the Evidence Says (2026)(opens in a new tab)
    Tier 3Web · thepeptidecatalog.com
  25. Dihexa: An Angiotensin IV Analog and Proposed HGF/c ...(opens in a new tab)
    Tier 3Web · superpower.com
  26. Dihexa Peptide Guide 2026: PNB-0408 Nootropic Evidence Review(opens in a new tab)
    Tier 3Web · thepeptidetoolkit.com · 2026
  27. Dihexa Peptide: What Research Actually Shows in 2026 | Klarovel(opens in a new tab)
    Tier 3Web · klarovel.com · 2026
  28. Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  29. What is dihexa peptide? - Creative Peptides(opens in a new tab)
    Tier 4Web · creative-peptides.com
  30. Effect of structure on the interactions between five natural antimicrobial compounds and phospholipids of bacterial cell membrane on model monolayers.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2014