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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 Importantly, all of this comes from animal and cell studies, and some of the original foundational papers have been retracted for data problems.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 investigated by researchers as an oral cognitive enhancer and has been proposed in preclinical reviews as a 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

129 findings extracted from the 19 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 22 animal findings, 4 in vitro findings, 4 expert opinion findings and 1 theoretical finding.

  • 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 test3

  • animalDihexa restored spatial learning and cognitive functions in the Morris water maze test3

  • animalDihexa improves performance in rodent learning-and-memory models4

  • 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-based4

Show 23 more findings

  • animalDihexa (PNB-0408) has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases5

  • animalPNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity5

  • animalMotor function at 8-16 weeks post-nerve repair significantly improved with MSC + Dihexa administrations into gastrocnemius muscle7

  • animalMSC + Dihexa administration mitigated foot flexion contractures7

  • animalPeroneal nerve function recovered quickly with return of function at one week (∼2.0) in all groups combined7

  • 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 combined7

  • animalIn models of cognitive deficit, dihexa improved performance on spatial working memory and passive avoidance tasks8

  • animalA Dihexa concentration of 1 μM confers optimal protection from acute treatment with neomycin or gentamicin in zebrafish larval lateral line hair cells10

  • animalDihexa has shown promise in facilitating the formation of new functional synaptic connections and augmenting memory consolidation in animal models of AD11

  • animalDihexa facilitates memory consolidation and retrieval11

  • animalDihexa improves cognition and increases synapses in rat models of cognitive dysfunction16

  • animalDihexa did not improve cognitive functions in rats with normal cognition16

  • animal8 of 9 studies found Ang IV and its analogs were effective in improving performance on spatial working memory and passive avoidance tasks16

  • animalAn independent 2021 study in APP/PS1 Alzheimer's-model mice replicated dihexa's procognitive effects through PI3K/AKT signaling17

  • in vitroDOTA-diHexa(NC-NC)-amide binding activity was 1.75-fold higher than DOTA-NAPamide in vitro14

  • in vitrodiHexa(NC-NC)-Gly-Lys(DOTA)-amide binding activity was 3.37-fold higher than DOTA-NAPamide in vitro14

  • in vitroDOTA-diHexa(CN-NC)-amide binding activity was 2.34-fold higher than DOTA-NAPamide in vitro14

  • in vitroUsing human HBL melanoma cells, diHexa(NC-NC)-Gly-Lys(DOTA)-amide binding activity was sixfold higher than DOTA-NAPamide14

  • expert opinionNo studies in humans have been published to date16

  • expert opinionNo studies have examined dihexa for age-related diseases16

  • 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 benefits16

  • expert opinionNo human clinical trials have been completed17

  • theoreticalDihexa has zero published human clinical trials4

How it works

Based on 32 animal findings, 17 in vitro findings, 7 expert opinion findings and 8 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

Show 56 more findings

  • animalThe amount of AngIV in mouse tissue increased after administration of Dihexa compared to wild-type group3

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

  • animalDihexa decreased activation of astrocytes and microglia3

  • animalDihexa markedly reduced levels of pro-inflammatory cytokines IL-1β and TNF-α3

  • animalDihexa increased levels of anti-inflammatory cytokine IL-103

  • animalDihexa activated the PI3K/AKT signaling pathway3

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

  • animalThe amount of AngIV in mouse tissue increased after the administration of Dihexa compared to that in the WT group3

  • animalDihexa increased the neuronal cells and the expression of SYP protein in APP/PS1 mice in Nissl staining3

  • animalDihexa decreased the activation of astrocytes and microglia3

  • animalDihexa markedly reduced levels of the pro-inflammatory cytokines IL-1β and TNF-α and increased the levels of the anti-inflammatory cytokine IL-103

  • animalDihexa activated the PI3K/AKT signaling pathway3

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

  • animalThe synaptogenic effects of angiotensin-IV-derived peptides are dependent on activation of the hepatocyte growth factor (HGF) / c-Met system4

  • animalBlocking c-Met abolishes the synapse-building effect4

  • animalSmall-molecule-derived hepatocyte-like cells displayed typical functional characteristics as mature hepatocytes in vitro and repopulating injured liver in vivo6

  • animalDihexa shows beneficial effects through AT4R activation8

  • animalDihexa pretreatment does not affect the amount of fluorescently tagged gentamicin that enters hair cells, indicating protection is mediated by intracellular events10

  • animalDihexa-mediated protection is attenuated by co-treatment with HGF antagonist 6-AH, indicating HGF activation is a component of the observed protection10

  • animalDihexa's protection is partially attenuated by co-treatment with inhibitors of downstream HGF targets Akt, TOR and MEK10

  • animalAddition of an amino group to the N-terminal of Dihexa attenuates the protective response10

  • animalDihexa induces dendritic arborization and synaptogenesis when stimulating the HGF/c-Met receptor system11

  • animalDespite higher affinity to MC1-R and excellent internalization in vitro, uptake by melanoma tumors in vivo was lower, possibly due to reduced tissue penetration14

  • animalDihexa activities have been linked to improved cognitive functions and increased dendritic arborization, spinogenesis, and synaptogenesis16

  • in vitroDihexa is seven orders of magnitude more potent than BDNF at building new connections between neurons in cultured hippocampal neurons4

  • in vitroDihexa and its angiotensin-IV-derived siblings promote the formation of new functional synapses in cultured hippocampal neurons4

  • in vitroCombining Vitamin C, Dihexa, and Forskolin (VDF) could substitute growth factors to induce hepatic specification6

  • in vitroDihexa is an analog of Ang IV8

  • in vitroDihexa is a hepatocyte growth factor agonist9

  • in vitroDihexa is a small molecule drug candidate that can allosterically activate the hepatocyte growth factor (HGF) cascade10

  • in vitroDihexa is chemically stable and blood-brain barrier permeable, unlike native HGF10

  • in vitroDihexa acts as a synthetic HGF mimetic by dimerizing with endogenous HGF to activate the HGF receptor and downstream signaling cascades10

  • in vitroBoth melanotic and amelanotic melanomas (over-)express the melanocortin-1 receptor (MC1-R), the target for alpha-MSH14

  • in vitroDimerized MSH analogs display increased receptor affinity compared to monomeric MSH14

  • in vitroUptake by cultured B16-F1 cells was rapid and almost quantitative14

  • in vitroDiOC6 (dihexa-oxacarbocyanine iodide) is an agent that labels the endoplasmic reticulum (ER)15

  • in vitroFRET spectra indicated energy transfer between DiOC6 and CPO but no significant transfer between NAO and CPO15

  • in vitroCPO and DiOC6 show similar pattern of subcellular localization15

  • in vitroCPO relocalization can occur during irradiation15

  • in vitroCPO-catalyzed photodamage to both ER and mitochondrial Bcl-215

  • in vitroDihexa binds with high affinity to the hepatocyte growth factor (HGF) and promotes mesenchymal-epithelial transition factor (c-Met) signaling16

  • 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 barrier17

  • expert opinionProposed mechanism is potentiation of hepatocyte growth factor (HGF) signaling at the c-Met receptor, driving synaptogenesis and spinogenesis at picomolar concentrations in vitro17

  • expert opinionDihexa binds with high affinity to HGF and potentiates its activity at c-Met receptor17

  • expert opinionDihexa and Nle1-AngIV induce hippocampal spinogenesis and synaptogenesis similar to HGF itself17

  • expert opinionNew dendritic spines form functional synapses measured electrophysiologically as increased miniature excitatory postsynaptic current frequencies17

  • expert opinionActivation of PI3K/AKT signaling supports neuronal survival and reduce apoptosis17

  • expert opinionDihexa is a neuroactive peptide that enhances brain-derived neurotrophic factor and HGF/c-Met pathways critical to neuroplasticity18

  • theoreticalDihexa is chemically N-hexanoic-Tyr-Ile-(6) aminohexanoic amide and is engineered from angiotensin IV4

  • theoreticalDihexa is an angiotensin IV analog5

  • 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 neurons11

  • theoreticalDihexa is a first-in-class compound derived from the pre-prototype molecule Nle1-angiotensin IV11

  • theoreticalDihexa is a small molecule AngIV-based compound that is metabolically stable and penetrates the blood-brain barrier12

  • theoreticalThe brain AngIV/AT4 receptor system coincides with the brain hepatocyte growth factor/c-Met receptor system12

  • theoreticalAngIV interacts with the AT4 receptor subtype, with links to the insulin-regulated aminopeptidase (IRAP)12

  • theoreticalActivation of the c-Met receptor can stimulate neurogenesis and protect against tissue insults in many types of cells including neurons16

Dosing

Based on 1 animal finding.

  • animalBrain RAS peptides including dihexa appear most effective administered intracerebroventricularly8

How the body handles it

Based on 12 animal findings, 1 expert opinion finding and 1 theoretical finding.

  • 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 mice3

  • animalDihexa can be orally administered and cross the BBB in APP/PS1 mice3

  • animalDihexa is orally active11

  • animalDihexa penetrates the blood-brain barrier11

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.11 for [(111)In]DOTA-diHexa(NC-NC)-amide14

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.26 for diHexa(NC-NC)-Gly-Lys([(111)In]DOTA)-amide14

Show 6 more findings

  • animalTumor-to-kidney ratios 4 hr postinjection were 0.36 for [(111)In]DOTA-diHexa(CN-NC)-amide14

  • animalTumor-to-kidney ratios 4 hr postinjection were 1.67 for [(111)In]DOTA-NAPamide14

  • animalDihexa crosses the blood-brain barrier based on rodent studies16

  • animalDihexa demonstrated a circulating half-life of 12.68 days after intravenous administration and 8.83 days after intraperitoneal administration in Sprague-Dawley rat studies17

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

  • theoreticalDihexa was designed to be metabolically stable and orally active while keeping procognitive activity4

Safety and side effects

Based on 1 animal finding, 4 expert opinion findings and 3 theoretical findings.

  • animalRadiolabeled alpha-MSH dimer peptides show marked increase of kidney uptake, explaining unfavorable in vivo ratios14

  • expert opinionNo studies in animals or humans have examined the long-term safety of dihexa16

  • 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 data17

  • expert opinionLong-term safety, particularly around chronic activation of a pathway involved in tumor biology, is entirely unstudied17

  • expert opinionThe 2013 McCoy paper carries a Notice of Concern17

  • theoreticalDihexa has no approved indication anywhere, no human efficacy data, no established human dose, and no long-term safety profile4

  • theoreticalDihexa via activation of HGF and c-Met could theoretically promote tumorigenesis and cancer progression16

  • theoreticalDihexa has a long half-life and there are theoretical concerns of c-Met activation leading to tumorigenesis and cancer progression16

What people use it for

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

  • animalPNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model5

  • animalDihexa administration can improve recovery of limb function following peripheral nerve damage in rat sciatic nerve transection-repair model7

  • animalDihexa is a promising candidate for adjunct therapy to promote limb functional recovery after surgical nerve repair7

  • animalDihexa is most effective close to the time of learning acquisition or retention testing8

  • animalDihexa holds clinical potential for mitigating chemical ototoxicity10

  • in vitroDihexa as part of VDF cocktail enabled hepatoblasts to expand and mature into functional hepatocyte-like cells6

  • in vitroDihexa is used to differentiate hepatoblasts to hepatocyte-like cells in vitro from human pluripotent stem cells9

  • 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 targeting14

Show 2 more findings

  • theoreticalDihexa may be efficacious as a treatment for Alzheimer's disease11

  • theoreticalDihexa shows promise in overcoming memory and motor dysfunctions by augmenting synaptic connectivity via the formation of new functional synapses12

Other findings

Based on 1 theoretical finding.

  • 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/mol17

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.

Using it with other compounds

Check a stack
  • SemaxComplementary

    May be complementary

    Semax raises BDNF/NGF and activates TrkB, while Dihexa works through HGF/c-Met — two distinct routes to enhanced neuroplasticity and neuroprotection that converge on the same nootropic goal.

    Tier 4Theoretical — not established

    Shares BDNF signaling · neurogenesis · anti inflammatory

  • NoopeptComplementary

    May be complementary

    Noopept boosts BDNF/NGF and modulates AMPA/TrkB signaling for cognition, whereas Dihexa uses the HGF/c-Met synaptogenic route. Different mechanisms aimed at the same memory-enhancement and neuroprotection endpoint.

    Tier 4Theoretical — not established

    Shares BDNF signaling · anti inflammatory

  • BPC-157Complementary

    No documented conflict

    BPC-157 reportedly interacts with the HGF/EGF/FGF growth-factor system and shares PI3K/Akt and mTOR signaling with Dihexa. While BPC-157 is mainly tissue-repair oriented, the overlapping growth-factor and anti-inflammatory pathways make it a plausible complementary partner for neuroprotection.

    Tier 4Theoretical — not established

    Shares mTOR PI3K · anti inflammatory

  • CerebrolysinComplementary

    May be complementary

    Cerebrolysin supplies broad neurotrophic-factor mimicry (TrkA/TrkB, BDNF/IGF-1) while Dihexa amplifies HGF/c-Met-driven synaptogenesis. Different upstream mechanisms both feeding PI3K/Akt survival and plasticity signaling, so they can reinforce each other for neuroprotection and cognition.

    Tier 4Theoretical — not established

    Shares BDNF signaling · mTOR PI3K · neurogenesis · anti inflammatory

  • DavunetideComplementary

    May be complementary

    Davunetide stabilizes microtubules and promotes neurite outgrowth/synapse formation via PI-3K/Akt, a structural complement to Dihexa's HGF/c-Met-driven spine formation. Two different mechanisms both supporting neuronal architecture and plasticity.

    Tier 4Theoretical — not established

    Shares mTOR PI3K · anti inflammatory

  • CortexinComplementary

    May be complementary

    Cortexin provides BDNF/NGF-like neurotrophic support and synaptic plasticity through a polypeptide mixture, complementing Dihexa's targeted HGF/c-Met synaptogenesis. Distinct mechanisms converging on neuronal survival and cognition.

    Tier 4Theoretical — not established

    Shares BDNF signaling · neurogenesis · anti inflammatory

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(vendor claim). 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 (preclinical rat studies)
  • Intraperitoneal (i.p.): up to 20 mg/kg (preclinical rat studies)

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. Dihexa: a striking preclinical nootropic with zero human evidence | Aminoscope(opens in a new tab)
    Tier 2Web · aminoscope.com · 2026
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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.

  14. 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
  15. Studies on the subcellular localization of the porphycene CPO.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2005
  16. Dihexa(opens in a new tab)
    Tier 3Web · alzdiscovery.org
  17. Dihexa Peptide: What Research Actually Shows in 2026 | Klarovel(opens in a new tab)
    Tier 3Web · klarovel.com · 2026
  18. Therapeutic Peptides in Orthopaedics: Applications, Challenges, and Future Directions.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  19. 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

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