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Cognitive & Neuroprotective

Dihexa

Angiotensin IV–derived oral research compound that boosts HGF/c-Met signaling and synapse formation in animals; no human trials.

RestrictedEvidence level 2 of 5: Animal data, minimal humanAlso: PNB-0408, N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide

Overview

Dihexa is a small synthetic molecule derived from angiotensin IV and developed at Washington State University as a potential Alzheimer's therapy. It acts by enhancing hepatocyte growth factor (HGF) signaling through its receptor c-Met, a pathway that drives dendritic spine growth and new synaptic connections. In rodent studies it restored learning and memory in models of cognitive impairment and was reported to be far more potent than BDNF at forming new synapses in cell culture. Unusually for a peptide-like compound, it is orally active and crosses the blood–brain barrier. However, no controlled human studies have been published, and because c-Met overactivity is involved in many cancers, long-term safety is a genuine and unresolved concern.

Classification
Synthetic angiotensin IV–derived oligopeptide analog (orally active)
Route
Oral (also transdermal/subcutaneous in non-validated protocols)
Half-life
Not characterized in humans

Mechanism of action

Primary targetHGF/c-Met receptor tyrosine kinase (positive modulator)
  1. Oral absorption, BBB entryLipophilic modifications allow oral bioavailability and blood–brain barrier penetration in animal studies.
  2. Binds HGFFacilitates HGF dimerization, increasing its ability to activate the c-Met receptor.
  3. c-Met activationReceptor tyrosine kinase signaling increases in hippocampal and cortical neurons.
  4. PI3K/Akt and MAPK signalingPro-survival and growth pathways drive cytoskeletal remodeling.
  5. Dendritic spine formationNew spines and synapses form, strengthening hippocampal circuits in rodent models.
Downstream effects
  • Synaptogenesis (animal data)
  • Improved rodent memory
  • Theoretical oncogenic risk

Researched for

  • Alzheimer's disease (preclinical)
  • Age-related cognitive decline
  • Parkinson's disease models
  • Neural injury recovery

Research notes

  • McCoy et al. (2013) showed dihexa improved spatial learning in scopolamine-impaired and aged rats.
  • Potency claims ("10 million times BDNF") come from in vitro spine-formation assays, not human outcomes.
  • Fosgonimeton (ATH-1017), a related HGF/c-Met positive modulator, did not meet its primary endpoint in the LIFT-AD Alzheimer's trial (2024).
  • c-Met is overexpressed in gastric, lung, liver and other cancers, so pro-growth signaling raises unquantified long-term risk.

Reported side effects

  • Vivid dreams
  • Headache
  • Insomnia or overstimulation
  • Unknown long-term effects (no human safety data)

Contraindications & cautions

  • Active or prior malignancy
  • Strong family history of cancer, especially c-Met–driven tumors
  • Pregnancy and breastfeeding
  • Age under 18

Lab monitoring

  • CBC, CMP
  • Liver panel (AST, ALT, ALP, GGT)
  • Fasting glucose, HbA1c
  • Age-appropriate cancer screening
  • Baseline and follow-up cognitive assessment

Dosing and pricing for Dihexa

Dosing references and compound pricing are available to established patients in the secure portal after a medical evaluation.

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