Dihexa (PNB-0408)
Dihexa — the "10-million-times-BDNF" nootropic peptide: retractions, zero human data, cancer-pathway risk

Class: peptide
Synonyms: Dihexa
PNB-0408
N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide
derived from Nle¹-angiotensin IV. MW ≈ 504.67. INCI: none
Function tags: nootropic / procognitive
synaptogenesis (synapse-building)
(preclinical only; heavily gray-market)
Overall evidence grade: F
WADA prohibited: no
Last updated: 2026-07-13

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."

## 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.

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

Legal status:
region: EU
status: Not FDA-approved (gray-market)
note: not approved anywhere; investigational research chemical. Not a cosmetic. No compounding pathway (reports indicate FDA removed it from interim Category-2 bulk-substance consideration).

Cosmetic claims:

Note: 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."
Status note: status: preclinical + retracted foundation + failed related clinical program; unlikely to improve without new, independent human data

Sources:
Retraction 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.
Original preclinical: Harding/Wright/McCoy — AngIV analogs restore cognition in scopolamine/aged rodents (JPET 2012–2013); Pederson 2001 (Regul Pept).
Independent corroboration of HGF/c-Met involvement — Sun et al. 2021.
Athira 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).
HGF/c-Met as an oncogenic pathway (general oncology literature). (No human Dihexa data as of 2026.)