Dihexa
| Category | Other Peptides |
| Goals | Cognition & Focus |
| Evidence level | Preclinical (rodent only; no human trials) |
| Legal status | Research-only — not approved for human use anywhere |
| FDA status | Not FDA-approved; not currently on 503A bulk lists |
| Half-life | Not well established in humans |
| Routes | Oral (designed for BBB penetration) · Subcutaneous |
| CAS / MW / Sequence | 1401708-83-5 · ~504.7 g/mol · Hexanoyl-Tyr-Ile-Ahx-NH2 |
| Last reviewed | 2026-06-05 |
In one line
A synthetic angiotensin IV-derived oligopeptide engineered for extreme potency at promoting synaptogenesis, studied only in animals for cognition — with serious unresolved safety and replication questions.
Evidence at a glance
All Dihexa efficacy data is preclinical (rodent); there are no human clinical trials. A foundational paper describing its HGF/c-Met mechanism was retracted in April 2025, and a related clinical-stage Alzheimer’s drug (fosgonimeton) failed its Phase 2/3 trial in 2024. The HGF/c-Met pathway it targets is also pro-cancer. Treat all human-use claims with strong caution. See Evidence Grading Explained and the Disclaimer.
Key Takeaways
- A synthetic, lipophilic oligopeptide (Hexanoyl-Tyr-Ile-Ahx-NH2) derived from angiotensin IV, designed to cross the blood-brain barrier and survive oral dosing.
- Reported in early work to be extraordinarily potent at inducing dendritic spine and synapse formation — orders of magnitude beyond its parent compound in vitro.
- Proposed mechanism is HGF/c-Met activation, but the key paper for this was retracted (2025).
- No human trials; not FDA-approved. Safety is essentially uncharacterized, and the target pathway has oncogenic associations.
- The most speculative and least-validated of the popular cognitive peptides — contrast with the clinically-used Semax and Selank.
What Is It
Dihexa (developmental code PNB-0408) is a synthetic oligopeptide derived from angiotensin IV (a fragment of the renin-angiotensin system implicated in memory). It is built from two hydrophobic residues (Tyr-Ile) capped with a hexanoyl group at the N-terminus and a 6-aminohexanoic amide at the C-terminus — modifications intended to make it lipophilic enough to penetrate the brain and stable enough to be taken orally, a property most peptides lack. It was investigated chiefly at Washington State University for cognitive and neurodegenerative applications and remains preclinical.
Mechanism of Action
Mechanisms are preclinical and now partly contested:
- HGF / c-Met activation (preclinical — contested) — proposed to bind hepatocyte growth factor and potentiate signaling through its receptor c-Met, driving synapse formation. The foundational paper for this mechanism was retracted in April 2025, so it should be treated as unconfirmed.
- Synaptogenesis / spinogenesis (animal/in-vitro) — reported to induce hippocampal dendritic spine and synapse formation, the basis for procognitive claims.
- Angiotensin IV / IRAP context (background) — derived from angiotensin IV, which interacts with insulin-regulated aminopeptidase (IRAP); the relevance of this to Dihexa’s effects is not fully resolved.
Limitations
Beyond the 2025 retraction of the mechanism paper, much efficacy data comes from a single research lineage and has not been broadly independently replicated. The HGF/c-Met pathway is implicated in tumor growth, an unresolved safety concern.
Evidence by Outcome
| Outcome | Evidence | Notes |
|---|---|---|
| Memory / learning (rodents) | Preclinical | Reversed scopolamine-induced deficits; aged-rat and ischemia models |
| Synaptogenesis | Preclinical | Potent spine/synapse formation in vitro and in rodents |
| Human cognition / Alzheimer’s | None (no human data) | Related clinical drug fosgonimeton failed its 2024 Phase 2/3 trial |
| Mechanism (HGF/c-Met) | Preclinical / Retracted | Key supporting paper retracted April 2025 |
| General “smart drug” claims | Anecdotal | No controlled human data |
Reported Dosing
Not medical advice
There is no established human dose for Dihexa, and no human safety data. Figures below are from rodent studies or allometric extrapolation only. See Reconstitution & Dosing Math.
| Route | Dose (reported) | Frequency | Cycle |
|---|---|---|---|
| Oral (rodent) | ~0.02–2 mg/kg/day | Daily | Study-dependent (e.g. up to 28 days) |
| Human (extrapolated only) | ~1.5–15 mg/day (allometric estimate) | — | No validated protocol |
| Subcutaneous | Reported anecdotally | — | No validated protocol |
Pharmacokinetics
Dihexa was specifically engineered for oral bioavailability and blood-brain-barrier penetration — rodent studies show oral dosing reverses cognitive deficits, implying meaningful CNS exposure. Quantitative human PK, including half-life, is not well established. See Half-Life & Pharmacokinetics.
Side Effects & Risks
- No human safety data exists — this is the central risk. Rodent studies up to ~1 mg/kg/day for 28 days reported no obvious hepato-, nephro-, or behavioral toxicity, but were not designed as toxicology studies.
- Oncogenic concern: the HGF/c-Met pathway it targets is a known pro-cancer pathway, making unsupervised use of a potent activator a serious theoretical risk.
- Mechanism uncertainty: the retraction of the key 2025 paper undermines confidence in the proposed mode of action.
- Sourcing risk: sold as a research chemical, so identity and purity vary widely — see Sourcing and Red Flags & Scams.
- See Side Effects & Risk Management.
Cycling
No evidence-based cycling standard exists, and there is no validated human protocol of any kind. See Cycling.
Stacks It Appears In
- Sometimes grouped with Semax and Selank in “cognitive peptide” discussions, though it is far less validated than either.
Comparisons
- Semax / Selank — both have Russian clinical use; Dihexa is preclinical only and carries greater unresolved safety questions.
Sourcing & Quality
Sold exclusively as a lyophilized “research chemical,” so identity and purity are not guaranteed. Evaluate quality before trusting a product: How to Read a CoA, Red Flags & Scams. Reconstitution and storage: Reconstitution & Dosing Math, Storage & Handling. No vendors are endorsed here.
Legal & Regulatory Status
(As of 2026-06-05.) Not FDA-approved for human use, and not approved by any regulatory authority worldwide. It is sold only as a research chemical and is not currently listed among FDA 503A bulk substances prohibited from compounding (lists updated Nov 2023 and Feb 2025). Status varies by country and it may be prohibited in tested sport. See Regulatory & Legal Status.
FAQ
Is Dihexa FDA-approved? No. It is not approved anywhere for human use and has never undergone human clinical trials.
Does Dihexa work in humans? Unknown. All efficacy data is from rodents, and a related clinical drug (fosgonimeton) failed its 2024 Alzheimer’s trial.
Is the HGF/c-Met mechanism confirmed? No. The foundational paper supporting it was retracted in April 2025, so the mechanism should be treated as unconfirmed.
Is it safe? There is no human safety data, and the target pathway has cancer associations — a notable unresolved concern.
References
- Wikipedia — “Dihexa” (angiotensin IV derivation, PNB-0408, structure).
- MedChemExpress / Selleck / InvivoChem — Dihexa CAS 1401708-83-5, formula C27H44N4O5, molar mass ~504.7.
- McCoy A.T. et al. (2013/2014), J. Pharmacol. Exp. Ther. / PMC4201273 — procognitive and synaptogenic effects via HGF/c-Met (note: associated mechanism paper later retracted, April 2025).
- Athira Pharma — LIFT-AD Phase 2/3 of fosgonimeton (Dihexa-derived) failed primary/secondary endpoints (announced 2024).
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