Dihexa

PNB-0408, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, angiotensin IV analogue

Cognitive & neuro

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Summary

Class: Synthetic small-molecule peptidomimetic derived from angiotensin IV; a capped tripeptide-like structure with a hexanoic acid head and an aminohexanoic amide tail that make it orally active and blood-brain-barrier penetrant
Mechanism: Reported to bind hepatocyte growth factor (HGF) and strongly amplify signalling through its receptor c-Met, driving the formation of new synapses in the hippocampus
Routes studied: Oral and subcutaneous (rats); intracerebroventricular (rats); oral and transdermal (community)
Dose range reported: Rats: 2 mg/kg/day oral or subcutaneous for 2–3 weeks restored memory in scopolamine and aged-rat models. Community reports: 8–45 mg/day oral or applied to skin in a carrier (DMSO or similar). No human dose exists
Half-life: Reported as long in rodents (stable in blood for over 12 hours, stable in brain homogenate), unusual for a peptide; human data none
Storage: Powder: room temperature or refrigerated, protect from light and moisture. Poorly water-soluble — typically dissolved in DMSO or oil, which is itself a handling concern
Regulatory status: Not approved anywhere. FDA compounding Category 2 (2023). No human trials registered as of review date

Doses are as reported in studies or by the community — never recommendations.

1What it is

Dihexa was designed in the laboratory of Joseph Harding and Jay Wright at Washington State University, published in 2012–2014. The starting point was angiotensin IV, a fragment of the blood-pressure hormone angiotensin that had surprising memory-enhancing effects in rats but broke down too fast to be useful. The group reshaped it into a stable, fat-soluble molecule that could be swallowed and cross into the brain. "Dihexa" refers to its two six-carbon (hexa) groups.

The headline claim that drew attention — that it is "seven orders of magnitude more potent than BDNF" at forming synapses in cell culture — comes from the inventors' own assay comparing spine formation, and should be read as a laboratory potency comparison in one assay, not as a measure of effect in a living brain. A spin-out company (Athira Pharma) took a related analogue, fosgonimeton (ATH-1017), into human trials for Alzheimer's disease; those trials failed in 2022–2024. Dihexa itself has never been given to humans in any published study.

2How it's thought to work

HGF/c-Met. Dihexa binds HGF and makes it a far more effective activator of its receptor c-Met, in cell assays and by inference in rat brain (Benoist 2014). HGF/c-Met signalling supports neuron survival, growth of dendrites and synapse formation.

Synaptogenesis. in cultured hippocampal neurons it increases dendritic spine density; in rats it is proposed to repair lost connections rather than just boost transmitter levels.

Angiotensin IV / IRAP. the parent compound binds insulin-regulated aminopeptidase (IRAP, also called the AT4 receptor); whether Dihexa retains meaningful IRAP activity is debated and the inventors favour the HGF mechanism.

Blocking c-Met abolishes the effect. in both cell culture and rat behavioural experiments, which is the strongest mechanistic evidence.

Proposed: teams up with hepatocyte growth factor to switch on its receptor, c-Met, prompting hippocampal neurons to form new synapses (animal data).Schematic — not to scale

3What the research shows

Memory in scopolamine-impaired and aged rats

Rats given scopolamine (a drug that blocks memory formation) and aged rats both showed restored spatial learning in the Morris water maze after oral or Dihexa at 2 mg/kg/day; the effect was blocked by a c-Met inhibitor (McCoy 2013, J Pharmacol Exp Ther; Benoist 2014, J Pharmacol Exp Ther). [1][2]

Synapse formation in cultured neurons

Marked increases in dendritic spine number and functional synapses in hippocampal neuron culture, dependent on HGF/c-Met (Benoist 2014). The "more potent than BDNF" comparison comes from here. [2]

Parkinson's disease model

In a rat 6-OHDA model, Dihexa improved motor function and preserved dopamine neurons, consistent with HGF/c-Met neuroprotection (Kawas 2017 and related).

Oral bioavailability and brain penetration

The 2013 work compared oral and subcutaneous dosing in rats and reported equivalent behavioural effects, with the compound detectable in brain tissue and stable in serum for hours (McCoy 2013). This is the basis for the claim that it is "orally active"; it has not been shown in any other species. [1]

Human cognition, Alzheimer's disease, "brain repair"

No human studies of Dihexa exist. The related analogue fosgonimeton did not meet primary endpoints in Phase 2/3 Alzheimer's trials (LIFT-AD, 2024) †, which is relevant negative evidence for the mechanism in humans.

4Reported side effects and interactions

Literature-reported

No formal toxicology or human safety data published. Rodent studies at effective doses reported no obvious toxicity over 2–3 weeks.

Community-reported

headache, "brain fog" or over-stimulation, fatigue, irritability, mood changes, reports of reduced effect over time; transdermal users report skin irritation from the solvent.

Theoretical. this is the main issue. HGF/c-Met is one of the most important growth and survival pathways in cancer; c-Met overactivation drives tumour growth and spread in many cancer types, and c-Met inhibitors are approved cancer drugs. A compound that amplifies HGF/c-Met signalling systemically for weeks has a plausible, untested cancer-promoting risk. Effects on the liver (where HGF is a key regenerative signal) and the cardiovascular system are also unknown.

Interactions. none studied. Theoretical opposition to c-Met inhibitor cancer therapies (crizotinib, cabozantinib, capmatinib, tepotinib).

Markers researchers commonly monitor

Marker	Why it's watched
No compound-specific laboratory markers are established and no human biomarker of c-Met activation is available in routine practice
Liver enzymes (ALT, AST)	HGF is a major liver growth signal; a sensible baseline.
Age- and risk-appropriate cancer screening status	the theoretical c-Met concern makes this the most relevant consideration in the literature's own framing, though no marker captures it directly.
Blood pressure	angiotensin-derived structure; no effect reported, worth confirming.
Cognitive self-ratings or standardised tests	the only efficacy readout.
General baseline panels (CBC, CMP)

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Dihexa is a hydrophobic powder, not a standard peptide, and does not dissolve in . Community practice uses DMSO, ethanol or an oil for oral or transdermal preparation; DMSO carries anything dissolved in it through skin, including contaminants. The standard calculator does not apply to this compound.

Open in calculator, pre-loaded →

6Commonly studied alongside

Nothing in the literature. In community discussion: Semax, Selank, Cerebrolysin and racetams as part of "nootropic stacks". No combination data.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved. Placed in Category 2 of FDA's compounding bulk substances list (2023), citing lack of safety data
European Union	Not authorised
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport	Not specifically named; S0 (non-approved substances) applies †

8Open questions

Is the HGF/c-Met mechanism sufficient and safe in humans? The failure of fosgonimeton is a caution.
Oncogenic risk of chronic systemic c-Met potentiation — completely unstudied.
Does oral Dihexa reach the human brain at meaningful concentrations?
Is the compound stable and correctly identified in research-market supply, given it is a non-standard small molecule?
Transdermal absorption through DMSO has never been measured; community dosing by this route is guesswork.

9References

1McCoy AT et al. (2013). Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. PubMed · DOI
2Benoist CC et al. (2014). The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-Met system. J Pharmacol Exp Ther. PubMed · DOI
3Benoist CC et al. (2011). Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs. J Pharmacol Exp Ther. PubMed · DOI
4Wright JW, Harding JW (2015). The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer's disease. J Alzheimers Dis. PubMed · DOI
5Kawas LH et al. (2011). Development of angiotensin IV analogs as hepatocyte growth factor/Met modifiers. J Pharmacol Exp Ther. PubMed · DOI
6FDA (2023). Bulk drug substances for compounding — dihexa category 2 listing. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

25 Oct 2026Profile published — awaiting medical review

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