📋 Pep IQ provides independent reference information for educational purposes only. Nothing here constitutes medical advice or treatment recommendation. All compounds require individual assessment. Consult a qualified physician before considering any peptide protocol.
Nootropic Peptide Angiotensin IV Derivative

Dihexa

PNB-0408 · N-hexanoic-Tyr-Ile-(6) aminohexanoic amide · Angiotensin IV Derivative

"A synaptogenic compound derived from angiotensin IV. Animal data shows strong effects on synapse formation and memory in disease models. Half-life of 13 days. Oral or transdermal active. No human trials conducted to date."

Type
Angiotensin IV derivative
Origin
Washington State University
Status
UK: not illegal to buy or possess · WADA: not specifically listed · US FDA: removed from Cat 2 Apr 2026 · PCAC review by Feb 2027
Half-life
~13 days · oral or transdermal
Protocol summary
Dose (extrapolated)
~10–45 mg/day oral
Route
Oral or topical
Cycle
4–8 weeks experimental
Community-reported
~10–45 mg/day oral · 4–8 week cycles
Doses extrapolated from rodent mg/kg — unvalidated in humans
How we read the evidence
Strong rodent data · zero published human trials · theoretical cancer concern via HGF/c-Met · highly experimental
Animal evidence

Genuine mechanism. Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is an angiotensin IV analog that acts as a hepatocyte growth factor (HGF) mimetic, binding c-Met receptors to drive synaptogenesis. Washington State University studies (Benoist et al.) showed potency 7+ orders of magnitude greater than BDNF in preclinical synaptogenesis assays. Reversed scopolamine-induced amnesia in Morris Water Maze in rats. Rodent doses 1–4 mg/kg orally, with surprisingly good oral bioavailability for a peptide-derived compound. Hippocampal cognitive recovery observed within 4–7 days of dosing.

Community & clinical practice

Community protocols are experimental and highly variable — there is no converged standard. The 1–4 mg/kg rodent dose extrapolates to roughly 10–45 mg/day for a 70 kg human, but no human PK or safety data exists to validate this. Reports range from microgram to milligram doses orally or topically. Most users run short cycles (4–8 weeks) at the lower end of the extrapolated range. Pep IQ does not endorse a specific dose because the human data simply does not exist.

Human trial data

No published human clinical trials. All efficacy data is rodent. The most studied model is scopolamine-induced amnesia, which is acute and reversible — extrapolation to chronic neurodegenerative disease (Alzheimer's, vascular dementia) remains unproven. Transgenic Alzheimer's models (APP/PS1, 3xTg-AD) would provide more disease-relevant data but published studies in those models are limited.

Regulatory status

Not FDA-approved. Sold only by research-peptide vendors. Not a prescription medicine. Theoretical cancer concern: HGF/c-Met signalling is implicated in tumour progression in some cancer types, so caution is advised in anyone with cancer history. No human cancer signal has been observed because no human data exists at all.

Convergence

Dihexa has a clean and interesting mechanism (HGF/c-Met agonist, synaptogenesis) and convincing rodent data — but the human evidence base is empty. Community doses are extrapolations from rat protocols, and the theoretical c-Met cancer concern is genuine even though unobserved in humans. Pep IQ flags this as one of the more experimental compounds on the platform: the science is genuine, the human data is absent, the long-term safety is unknown. Members considering Dihexa should weigh that absence carefully against the cognitive enhancement claim.

Origin & The Claim

The 7-million-times-BDNF nootropic

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) was developed at Washington State University by Joseph Harding and Barbara McDaniel, primarily studying the role of angiotensin IV and its receptor AT4 (now identified as HGF receptor, c-MET) in cognitive function. Dihexa is a superagonist at HGF receptors — a derivative of angiotensin IV engineered for improved stability and blood-brain barrier penetration.

The claim that launched it into nootropic consciousness: in the Morris water maze (spatial memory test), Dihexa produced cognitive improvements at concentrations approximately 7 million times lower than BDNF (Brain-Derived Neurotrophic Factor) was required to produce equivalent synaptogenic effects. The mechanism: HGF/c-MET signalling promotes dendritic arborisation, synaptogenesis, and neurotrophic support through mechanisms that converge on BDNF-like downstream effects but operate through a different receptor pathway.

Two additional properties make Dihexa unusual: (1) it is orally bioavailable and crosses the blood-brain barrier — most peptides fail both tests; (2) it has a half-life of approximately 13 days — extraordinarily long for a peptide, likely due to its lipophilic hexanoic acid modification. These pharmacokinetic properties make it uniquely practical as a peptide nootropic, if the efficacy translates to humans.

Important caveat on the "7 million times" claim: This comparison is between in vitro assay conditions — the concentration of Dihexa required to produce a measurable synaptogenic effect vs BDNF. It does not mean Dihexa is 7 million times more effective as a cognitive enhancer. BDNF does not easily cross the blood-brain barrier and has poor pharmacokinetics; Dihexa's comparison advantage includes these factors. The headline number captures attention but should not be taken as a direct measure of clinical potency.

Mechanism

HGF receptor agonism — synaptogenesis from a new angle

How Dihexa Works

1
HGF receptor (c-MET) superagonism: Dihexa acts as a superagonist at c-MET (the hepatocyte growth factor receptor), which is expressed throughout the brain. HGF/c-MET signalling promotes neurite outgrowth, dendritic branching, and synapse formation through the PI3K/Akt and MAPK/ERK pathways — the same downstream signals that BDNF activates through TrkB, but accessed through a completely different receptor.
2
Blood-brain barrier penetration: Most peptides fail to penetrate the blood-brain barrier due to their hydrophilicity and molecular weight. Dihexa's lipophilic hexanoic acid modification and small size enable passive BBB diffusion — the same challenge that prevents BDNF itself from being a practical therapeutic despite its well-established neuroprotective effects.
3
Synaptogenesis — structural changes: In animal models, Dihexa administration produced measurable increases in dendritic spine density and synapse number in hippocampal neurons. These are structural changes to neural architecture — not just functional modulation — which may explain why some community users report effects that persist well after dosing stops.
4
Alzheimer's models: In scopolamine-induced amnesia models and aged rat cognitive decline models, Dihexa significantly reversed learning and memory deficits. These are the animal models most relevant to neurodegenerative disease rather than healthy cognitive enhancement.

The 13-day half-life is a double-edged characteristic. It enables infrequent dosing (some users report dosing once per week or less). But it also means that if adverse effects occur, they cannot be rapidly reversed by stopping the compound. The accumulation over time with repeated dosing must be considered. Community protocols typically use conservative doses with long intervals precisely because of this pharmacokinetic profile.

Safety — The Long Half-life Problem

Risks & the irreversibility concern

🚨
No human safety trials. 13-day half-life means adverse effects cannot be rapidly reversed. This combination requires exceptional caution. Unlike peptides that clear in hours, any adverse reaction to Dihexa persists for weeks. The c-MET receptor has roles in cell proliferation across multiple tissues — systemic c-MET superagonism at high doses could theoretically promote tumour growth. No long-term safety data exists.
Serious
Irreversible effects from long half-life — 13 days means any side effect (anxiety, irritability, cognitive effects, or unknown systemic effects) will persist for 2–4 weeks minimum before the compound clears. There is no antidote. Start extremely low and observe for extended periods.
Unknown
c-MET activation and cancer risk — c-MET is a proto-oncogene. HGF/c-MET signalling is involved in tumour growth and metastasis. Whether Dihexa's c-MET agonism at neurotrophic doses poses cancer risk is completely unknown. Contraindicated in anyone with active or recent malignancy.
Unknown
Cumulative accumulation — repeated dosing accumulates the compound. The relationship between cumulative dose and effect/toxicity has not been characterised in humans.
Moderate
Anxiety and irritability — reported at higher doses. May relate to excessive HGF signalling or indirect effects on monoamine systems. Dose-dependent and resolves after clearance — but clearance takes weeks.