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Explore  /  Dihexa (PNB-0408)
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Dihexa (PNB-0408)

F
lead outcome
Synaptogenesis / cognition (the marketed use)
grades vary by outcome ↓
Peptide
also called — Dihexa · PNB-0408 · N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide · derived from Nle¹-angiotensin IV. MW ≈ 504.67. INCI: none
nootropic / procognitivesynaptogenesis (synapse-building)(preclinical only; heavily gray-market)

The most hyped nootropic peptide — and the register's starkest "spectacular claims, collapsed foundation" case. Three points define this entry, and they close the cognitive cluster opposite Cerebrolysin (#43): (1) it rode a jaw-dropping claim — "10 million times more potent than BDNF" at building synapses; (2) its foundational mechanism papers were retracted in 2025 for fabricated data, and the scientist responsible went on to run a biotech whose related drug failed its Alzheimer's trials; (3) it has zero human data and targets a pathway (HGF/c-Met) that is a validated cancer driver. Where Cerebrolysin is "most-studied but contested," Dihexa is "most-hyped but hollow."

In brief

Dihexa is a synthetic angiotensin-IV-derived peptide engineered to be orally active and cross into the brain, studied as a synapse-building (synaptogenic) cognitive enhancer via the HGF/c-Met growth-factor pathway. It became famous on a spectacular claim — ~10 million times more potent than BDNF at driving synaptogenesis in slice assays — which made it a nootropic-underground legend. The honest picture is sobering: all evidence is preclinical (cells and rodents), there are zero human trials, and the foundational mechanism papers were retracted in 2025 for fabricated data, with the responsible scientist (Leen Kawas) found "solely responsible" alongside the lab head. That same scientist ran Athira Pharma, whose related HGF/c-Met drug fosgonimeton failed its Alzheimer's trials — the only clinical test of this lineage, and it flopped. Add no safety data, a very long half-life, and the fact that HGF/c-Met is a validated cancer driver, and Dihexa becomes the register's clearest cautionary tale: an extraordinary claim resting on a collapsed foundation. It closes the cognitive cluster as the opposite of Cerebrolysin (#43) — not "lots of contested data," but "almost no legitimate data at all."

Legal standing, by region
European Union
Not FDA-approved (gray-market)

not approved anywhere; investigational research chemical. Not a cosmetic. No compounding pathway (reports indicate FDA removed it from interim Category-2 bulk-substance consideration).

Evidence, by outcome
How we grade →

An honest grade per outcome — drawn from the evidence, not any catalogue. Hype and undemonstrated marketing claims grade low.

OutcomeEvidence base · effectGrade
Synaptogenesis / cognition (the marketed use)
Zero human data; the headline potency claim traces to retracted, fabricated work
Preclinical only: rodent cognitive-restoration (scopolamine/aged) + slice synaptogenesis; "10M× BDNF" claim
F
HGF/c-Met mechanism
Best treated as an unproven working hypothesis, not established fact
Original binding paper (Kd 65 pM) retracted 2025; some independent HGF/c-Met corroboration (Sun 2021)
F
Clinical translation (via the lineage)
The one clinical program on this pathway/lineage failed — a strong negative signal
The related drug fosgonimeton failed ACT-AD + LIFT-AD (no better than placebo)
F
Human efficacy or safety (Dihexa itself)
No trials, no safety profile, very long duration → adverse effects not rapidly reversible
None
F
Safety / oncologic risk
HGF/c-Met is a validated cancer-driver pathway; chronically potentiating it for enhancement is a real theoretical risk, unquantified in humans
Pathway-level concern
Disclosure

Vallydia sells its own cosmetic serums, and some ingredients graded here belong to the same categories as those products. Grades are drawn from the published evidence by the method we publish, and applied to our own ingredients on the same terms — our copper-peptide serum is graded no more kindly than the peptides it competes with. We disclose the interest so you can weigh it.

Trade names shown here (for example Matrixyl, Argireline, Syn-Ake) are the property of their respective owners and are used only to identify the ingredient under discussion. Their appearance implies no affiliation with, or endorsement by, the proprietor.

Evidence changes

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Identity

a small synthetic peptide engineered from angiotensin IV (a fragment of the renin-angiotensin system long linked to memory in animals). Its parent, Nle¹-AngIV, showed cognitive effects but poor bioavailability; Dihexa was built to fix that — to be orally active and blood-brain-barrier-penetrant. Developed at Washington State University by Joseph Harding and John Wright. It's small enough (MW ~505) to reach the brain, and is studied as a synaptogenic ("synapse-building") compound.

Mechanism (as proposed)

Dihexa is thought to potentiate HGF/c-Met signaling — the hepatocyte-growth-factor pathway that promotes dendritic-spine formation and synaptogenesis — thereby "building new synapses" rather than merely sharpening existing function (the basis of its mystique). In cultured hippocampal neurons, Dihexa and related AngIV analogs increase spine density, and that effect is abolished when HGF/c-Met is blocked — the main evidence the pathway matters. However, the paper that originally proposed direct high-affinity HGF binding was retracted for fabricated data, so the precise molecular interaction is contested and should be read as a working hypothesis. The pathway is biologically real and independently implicated; the specific mechanistic claims for Dihexa are not securely established.

Chemical identifiers

Cross-reference identifiers for the authoritative external databases — not a recipe, and nothing about how to use it.

PubChem CID129010512
InChIKeyXEUVNVNAVKZSPT-JTJYXVOQSA-N
SMILESCCCCCC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCCCCCC(=O)N
UNII9WYX65A5C2

via PubChem exact-name match (Dihexa) · high confidence

Sources — 5 cited
01Retraction notices (April 2025): Benoist et al. 2014 (JPET, HGF/c-Met mechanism, Kd 65 pM) and Kawas et al. 2012 — retracted for falsified/fabricated data (WSU investigation; Kawas & Harding responsible). McCoy 2013 — expression of concern.
02Original preclinical: Harding/Wright/McCoy — AngIV analogs restore cognition in scopolamine/aged rodents (JPET 2012–2013); Pederson 2001 (Regul Pept).
03Independent corroboration of HGF/c-Met involvement — Sun et al. 2021.
04Athira Pharma / fosgonimeton: ACT-AD Phase 2 (2022) and LIFT-AD Phase 2/3 (2024) failures (Stat/FierceBiotech/BioSpace/ALZFORUM); Kawas resignation 2021 (dissertation image alteration).
05HGF/c-Met as an oncogenic pathway (general oncology literature). (No human Dihexa data as of 2026.)
Updated 2026-07-13 (status: preclinical + retracted foundation + failed related clinical program; unlikely to improve without new, independent human data)

Grades reflect the published evidence, not our interest. No dosing, reconstitution, or administration is published for research compounds — that restraint is deliberate.

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