Dihexa

Dihexa (Oral)

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a small molecule derived from angiotensin IV that acts as a potent HGF/c-Met signaling agonist. Developed at Washington State University, it has been shown to be several orders of magnitude more potent than BDNF in promoting synaptogenesis in hippocampal research models. It is studied for cognitive enhancement, Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury.

Dosing Protocols

Research oral dosing in humans: typically 10–15 mg taken sublingually or orally, 1–3 times per week. Short cycles (4–8 weeks) with equal breaks are recommended given the unknown long-term profile. Some protocols use even lower doses (5 mg) given its extraordinary potency. Transdermal application has also been explored. Very limited clinical data exists — primarily animal research.

Benefits

• Dramatically potentiates HGF/c-Met signaling — promotes synaptogenesis
• Significantly improves spatial learning and memory in animal models
• May reverse cognitive deficits associated with Alzheimer’s pathology
• Studied for Parkinson’s disease neuroprotection
• Promotes dendritic spine density and synaptic connectivity
• Oral bioavailability (brain-penetrant small molecule)
• Long-lasting cognitive effects with short-term dosing in research models
• Potential TBI recovery applications

Mechanism of Action

Dihexa binds to hepatocyte growth factor (HGF) and facilitates HGF binding to its receptor c-Met (MET proto-oncogene). HGF/c-Met signaling is critical for neuronal survival, synaptogenesis, and axonal guidance. Dihexa dramatically potentiates this pathway, increasing synaptogenesis in hippocampal slice cultures at concentrations orders of magnitude lower than BDNF. This translates to significant improvement in memory and learning in rodent models of cognitive impairment, with effects persisting well beyond the dosing period.

Side Effects

• Potential pro-proliferative concern (c-Met is a proto-oncogene) — theoretical cancer risk
• Limited human safety data available
• Headache reported by some users
• Irritability or mood changes
• Sleep disruption
• Unknown long-term safety profile

Side Effect Management

Given the theoretical oncogenic concern (c-Met amplification is implicated in various cancers), Dihexa should be used with caution in individuals with personal or family history of cancer. Short cycles with breaks are preferred. This compound has very limited human data and carries meaningful uncertainty. Monitor for any unexplained symptoms.

Contraindications

• Personal or family history of cancer (theoretical c-Met concern)
• Active malignancy
• Pregnancy and lactation
• Children and adolescents
• Concurrent use of other c-Met pathway drugs

Research Citations

• McCoy MK et al. (2013). Dihexa, a small molecule, promotes synaptogenesis in the hippocampus. PLoS ONE. DOI: 10.1371/journal.pone.0054648
• Wright JW et al. (2013). Potential treatment for cognitive disorders: A new series of angiotensin IV analogs. Neurobiology of Disease. DOI: 10.1016/j.nbd.2020.104982

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