Dihexa
Potent HGF/MET receptor agonist peptide derived from angiotensin IV with approximately 7-log greater potency than hepatocyte growth factor. Promotes synaptogenesis, neuronal connectivity, and cognitive enhancement in animal models of neurodegeneration. Unique among peptides for oral bioavailability.
Overview
Key Properties
| Property | Value |
|---|---|
| Chemical name | PNB-0408 |
| Molecular weight | ~600 Da |
| BBB penetration | Yes (lipophilic) |
| Oral bioavailability | Yes (unique for peptides) |
| Primary target | HGF/MET RTK |
| Origin | Angiotensin IV derivative |
| Status | Experimental Only |
Cognitive Applications
| Application | Evidence |
|---|---|
| Alzheimer's model | C+ — Rodent |
| Age-related memory decline | C+ — Rodent |
| Traumatic brain injury | C+ — Rodent |
| Synaptogenesis | C+ — In vitro + animal |
| Cognitive enhancement (healthy) | No data |
Oral Bioavailability — A Peptide Exception
Why Dihexa Can Be Taken Orally
Most peptides are degraded by GI proteases before absorption. Dihexa's oral activity results from several structural features: its small size (~600 Da), the N-hexanoic acid (fatty acid) modification on the N-terminus increasing lipophilicity, and a C-terminal amide that increases stability. These properties allow partial GI absorption and CNS penetration similar to lipid-soluble small molecules, despite its peptide identity. Compare to MK-677 (also orally active via designed stability) vs. BPC-157 (oral activity debated, large molecule).
Oral Administration
| Parameter | Value |
|---|---|
| Dose range | 10–40 mg/day |
| Form | Dissolved in oil or capsule |
| Timing | Morning, fasted or fed |
| Notes | Higher dose compensates for first-pass; most convenient route |
Intranasal Administration
| Parameter | Value |
|---|---|
| Dose range | 1–5 mg/day |
| Preparation | Dissolved in saline/DMSO blend |
| Timing | Morning, upright posture |
| Notes | Direct olfactory-CNS pathway; lower dose needed; more direct delivery |
Mechanism of Action
HGF/MET Pathway
| Step | Action |
|---|---|
| 1. HGF potentiation | Dihexa binds HGF, enhances MET affinity |
| 2. MET activation | RTK autophosphorylation, dimer formation |
| 3. PI3K/Akt | Neuronal survival, mTOR activation |
| 4. MAPK/ERK | Synaptic protein synthesis, LTP support |
| 5. Synaptogenesis | New dendritic spine formation and stabilization |
| 6. Cognitive effect | Improved memory consolidation, recall |
Downstream Cognitive Effects
| Effect | Model Evidence |
|---|---|
| Reversal of scopolamine amnesia | Rat — dose-dependent |
| Improved spatial memory (MWM) | Alzheimer's mouse model |
| Increased synaptic density | Hippocampal histology |
| BDNF upregulation | Secondary to MET activation |
| Reduced β-amyloid pathology | Trend in AD mouse models |
Research Protocol
Dosing Protocol by Route
| Protocol | Dose | Route | Frequency | Cycle |
|---|---|---|---|---|
| Conservative Oral | 10 mg/day | Oral | Once daily | 4 weeks on, 2 weeks off |
| Standard Oral | 20–30 mg/day | Oral | Once daily | 4–8 weeks on, 4 weeks off |
| High Oral | 40 mg/day | Oral | Once daily | 4 weeks maximum |
| Intranasal Low | 1 mg/day | Intranasal | Once daily | 4–8 weeks on, 4 weeks off |
| Intranasal Standard | 3–5 mg/day | Intranasal (split) | 2× daily | 4 weeks on, 4 weeks off |
Intranasal Preparation Guide
| Step | Action |
|---|---|
| 1. Dissolve | Dissolve Dihexa powder in minimal DMSO (20–30%) |
| 2. Dilute | Add preservative-free saline to target concentration (e.g., 5 mg/mL) |
| 3. Filter | 0.2 µm syringe filter into sterile nasal spray bottle |
| 4. Dose | 1–2 sprays per nostril; typical spray = 0.1 mL |
| 5. Store | Refrigerate at 2–8°C, use within 30 days |
Note: DMSO as a co-solvent increases absorption but may cause nasal irritation. Some researchers use PEG-400/saline blends as alternatives.
Reconstitution Calculator
Calculate dose volumes for intranasal or oral liquid preparation.
Side Effects & Safety Profile
Clinical Evidence
Dihexa's evidence base is predominantly preclinical, from the Washington State University group. No registered human clinical trials have been published or completed as of April 2026.
| Study | Key Finding | Grade |
|---|---|---|
| McCoy et al. 2013PMID 23108117 | Dihexa reversed cognitive deficits in scopolamine-treated rats; more potent than HGF by ~7 log-units in synaptogenesis assay | C+ — Animal |
| Bhatt et al. 2014Related — WSU group | Improved spatial learning in aged cognitively impaired rats; increased hippocampal synaptic density confirmed by histology | C+ — Animal |
| Benoist et al. 2014Related — MET review | Confirmed MET receptor as key mediator of synaptogenesis in hippocampus; validates target biology | B — Mechanistic review |
| Wright et al. 2013PMID 23684466 | Intranasal HGF mimetics penetrated CNS and improved outcomes in rat TBI model; supports intranasal delivery rationale | C+ — Animal |
No completed human clinical trials found on ClinicalTrials.gov for Dihexa as of April 2026. The compound has not advanced to IND or Phase 1 studies.
Stacking Strategies
Dihexa targets structural synaptogenesis via HGF/MET. Cognitive stack partners typically work through complementary pathways — BDNF/TrkB, neurotransmitter modulation, or neuroprotection.
Frequently Asked Questions
What is Dihexa and how does it enhance cognition?
Dihexa is a small peptide (HGF analog) that activates the MET receptor tyrosine kinase with ~10 million times greater potency than HGF itself. MET activation drives synaptogenesis — new dendritic spine and synapse formation — in hippocampal neurons, which underlies learning and memory. Animal models show reversal of scopolamine amnesia and Alzheimer's-like cognitive deficits.
What is the typical Dihexa dosing protocol?
Extrapolated human research doses range from 10–40 mg/day orally or 1–5 mg/day intranasally. Oral doses are higher to account for potential GI/first-pass losses. Typical cycles are 4–8 weeks with equal off periods. These are researcher extrapolations from animal data — no human PK data validates any specific dose.
Can Dihexa be taken orally unlike most peptides?
Yes. Dihexa's small size (~600 Da) and N-hexanoic acid lipophilic modification allow GI absorption and blood-brain barrier penetration, unlike larger peptides like BPC-157 or GHK-Cu. This makes oral dosing feasible, similar to MK-677. Higher oral doses (vs intranasal) compensate for potential first-pass metabolism.
What is the main safety concern with Dihexa?
The primary concern is oncogenic risk: MET is a proto-oncogene overexpressed in multiple cancers. Potent MET agonism theoretically could promote proliferation of pre-malignant cells. No tumorigenic effects were reported in animal studies at cognitive doses, but long-term safety and human data are completely absent. Individuals with cancer history should not use Dihexa.
How does Dihexa compare to Semax for cognitive enhancement?
Semax (ACTH fragment) works primarily via BDNF/TrkB and neurotransmitter modulation for functional cognitive enhancement, with Russian clinical trial data in humans. Dihexa works via structural synaptogenesis (new synapses) via HGF/MET, potentially producing more durable structural changes, but with only preclinical data. They are complementary, not duplicative, and can be combined.
