# Dihexa

Rating: Speculative — Little primary evidence yet: mechanism, anecdote or tradition
Type: Compound
Updated: 2026-10-15
Canonical: https://heretic.bio/articles/dihexa-n-hexanoic-tyr-ile-6-aminohexanoic-amide.html

> Dihexa is an angiotensin-IV-derived oligopeptide sold to nootropic users on claims it is orders of magnitude more potent than BDNF. That foundation is compromised: the key papers are retracted or under expressions of concern, the related drug fosgonimeton failed its pivotal Alzheimer's trial, and no human study of dihexa exists. HGF/c-Met activation plus a multi-day half-life also raises a serious theoretical cancer risk.

> **Aliases:** N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, NHex, Dihexa **Sequence:** N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (oligopeptide derivative of angiotensin IV) **Molecular Weight:** 504.7 Da **Chemical Formula:** C₂₇H₄₄N₄O₅ **Origin:** Developed at Washington State University; derived from angiotensin IV analogs

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## Overview

Dihexa is a synthetic oligopeptide derived from **angiotensin IV** , engineered for **high metabolic stability** and **blood-brain barrier (BBB) penetrance**. It became famous in nootropic communities as "seven orders of magnitude more potent than BDNF" at spinogenesis — a claim that traces to papers now **retracted or under formal expressions of concern** (see Research Integrity Record).

**Evidence Level: LOW.** Preclinical only. **No published human studies exist; none are registered on ClinicalTrials.gov as of August 2026.** The mechanistic rationale (HGF/c-Met activation) was formally retracted in April 2025, and the founding lab's commercial successor failed its pivotal Alzheimer's trial and abandoned the target. Severe theoretical safety concerns. NOT FDA-approved.

> ⚠️ **CRITICAL WARNING:** Dihexa activates HGF/c-Met — a pathway directly implicated in tumorigenesis, cancer metastasis, and poorer prognosis. No long-term safety data exist in any species. **Extreme caution warranted.**

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## Research Integrity Record (2021–2025) — the part vendor sites omit

The Dihexa evidence base collapsed in slow motion, and most peptide-vendor literature has not caught up:

Paper | Status | Date  
---|---|---  
McCoy et al. 2013 (JPET 344:141–154, PMID [23055539](https://pubmed.ncbi.nlm.nih.gov/23055539/)) — foundational procognitive/aged-rat paper | **Expression of Concern** | 2021 (JPET 378(3):313; PMID [34551989](https://pubmed.ncbi.nlm.nih.gov/34551989/))  
Benoist et al. 2014 — HGF/c-Met dependence of synaptogenesis (the _mechanism_ paper) | **RETRACTED** | April 2025 (retraction notice [PMC13095468](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13095468/))  
Kawas et al. 2012 — AngIV analog development | **RETRACTED** | April 2025  
Four JPET papers from Wright/Harding lab overall | Formal expressions of concern | 2021  
  
  * **January 6, 2025 — Athira Pharma paid $4,068,698** to settle DOJ False Claims Act allegations: the company failed to disclose research-misconduct allegations (image manipulation by then-CEO Leen Kawas in dissertation + published papers) in NIH grant applications covering 2016–2021. Whistleblower Andrew P. Mallon received $203,434.
  * **Net effect:** the "7 orders of magnitude more potent than BDNF" spinogenesis claim traces directly to the affected papers. The HGF/c-Met mechanism framing remains **corroborated by some independent labs** (e.g., Chen et al. 2022 APP/PS1 mouse study via PI3K/AKT), but the dramatic quantitative claims should be treated as unverified.



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## Mechanism of Action

### Primary (per retracted/at-risk papers): HGF/c-Met Activation

  * Binds **Hepatocyte Growth Factor (HGF)** , facilitates **HGF dimerization** → c-Met receptor signaling → PI3K/AKT
  * HGF/c-Met is largely inactive in healthy adult learning but upregulated after brain injury/stroke/neurodegeneration



### Downstream Effects (claimed)

  1. Synaptogenesis — new functional synapses
  2. Dendritic arborization
  3. Spinogenesis — the famous "~3-fold spine increase" figure (McCoy 2013: ~15 → ~41 spines/50 µm dendrite) comes from the paper under expression of concern
  4. Neurogenesis, synaptic plasticity



### Mechanism status

The Benoist 2014 antagonist-blockade experiment (HGF antagonist "Hinge" abolished effects), which was the main confirmation that effects are HGF/c-Met-mediated, is **formally retracted**. Treat the entire mechanism section as provisional.

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## Primary Uses & Applications (Research Only)

Application | Evidence Level | Notes  
---|---|---  
**Cognitive enhancement** | Preclinical (at-risk papers) | Scopolamine-impaired rats, McCoy 2013 (EoC)  
**Age-related cognitive decline** | Preclinical (at-risk papers) | Aged rats, oral 2 mg/kg/day (EoC)  
**Alzheimer's models** | Independent preclinical | APP/PS1 mice via PI3K/AKT — Chen et al. 2022, _Mol Neurobiol_ , [PMC8615599](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615599/) (independent of WSU lab)  
**Zebrafish otoprotection** | Independent preclinical | Uribe/Kawas/Harding 2015, _Front Cell Neurosci_  
**Parkinson's / stroke / TBI** | Preclinical (at-risk papers) | Successor program dead — see below  
  
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## Clinical Evidence

### Human Studies

**NONE.** No published human studies; no registered trials on ClinicalTrials.gov (searched August 2026 — zero results). No Phase 1, no human PK data.

### Successor Program: fosgonimeton (ATH-1017) — FAILED and abandoned

The structurally related HGF/c-Met modulator from Athira Pharma was the closest dihexa-class molecules ever got to human proof of concept. The outcome is the most human-relevant data point in the entire class:

Trial | Design | Result  
---|---|---  
**LIFT-AD** ([NCT04488419](https://clinicaltrials.gov/study/NCT04488419), Ph 2/3) | 26 wk, fosgonimeton 40 mg SC daily vs placebo, n=287 efficacy analysis (549 enrolled), mild-moderate AD, no concurrent AChEIs | **FAILED primary endpoint** (Global Statistical Test = ADAS-Cog11 + ADCS-ADL23); missed key secondaries; numerical but nonsignificant biomarker trends (Sept 2024). Full publication: [PMC12701236](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12701236/)  
**ACT-AD** ([NCT04491006](https://clinicaltrials.gov/study/NCT04491006), Ph 2) | 26 wk, 40/70 mg, on AChEIs | Missed primary/secondary endpoints; monotherapy subgroup showed −28 ms ERP P300 latency improvement (exploratory)  
**PD/DLB Ph 2** ([NCT04831281](https://clinicaltrials.gov/study/NCT04831281)) | 40/70 mg | **Terminated** Dec 2022 at 28/75 enrolled  
  
**Aftermath:** mass layoffs (2024), pivot to oncology — in-house neuro pipeline reduced to ATH-1105 (ALS, small molecule, pre-Ph2), in-licensing of lasofoxifene (SERM, Ph 3 breast cancer) Dec 2025, and **rebrand to LeonaBio (ticker LONA) Jan 9, 2026**. The company that originated dihexa no longer develops HGF/c-Met modulators for cognition. This is a class-level negative signal, not proof of futility — but it removes the "successor drug in clinical trials" argument entirely.

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## Uses

> ⚠️ **NO ESTABLISHED HUMAN DOSING.** Dihexa is NOT approved for human use. Animal research doses only.

### Pharmacokinetics (Rats)

  * **Half-life:** extremely long — **12.68 days (IV)** , **8.83 days (IP)** — a property that _amplifies_ long-term risk concerns (tissue accumulation)
  * **BBB penetration:** confirmed in rodents
  * **Human PK:** none exists
  * **Formulation caveat:** animal studies dissolved Dihexa in **75% DMSO**
  * Gray-market "oral capsule" claims lack any peer-reviewed human bioavailability data; SC is the only route used in preclinical work



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## Safety Profile

> ⚠️ **SERIOUS SAFETY CONCERNS**

Aspect | Assessment  
---|---  
**Tumorigenesis risk** | ⚠️ **HIGH CONCERN** — HGF/c-Met is a well-established pro-cancer axis (overexpressed in most solid tumors; drives invasion/metastasis); deliberate activation + multi-day tissue half-life = compounded risk  
**Human safety data** | ⚠️ **NONE**  
**Long-term animal safety** | ⚠️ **NONE**  
**Formulation** | ⚠️ 75% DMSO vehicle in animal studies  
**Drug interactions** | ⚠️ **UNKNOWN**  
**Active cancer** | ⚠️ Absolute contraindication (theoretical but well-founded)  
**Cancer history** | ⚠️ Successor-drug trials excluded such patients  
**Overall** | ⚠️ **NOT RECOMMENDED for human use outside trials** — and no trials exist  
  
### Why the cancer concern is warranted

HGF/c-Met overexpression correlates with tumorigenesis, metastasis, and poor prognosis across cancer types. A metabolically stabilized, BBB-penetrant, week-scale-half-life activator of this axis is a fundamentally risky design — a caution that applies regardless of the retraction record.

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## Regulatory Status (2026)

  * **Not FDA-approved; no IND** for dihexa itself.
  * **April 22, 2026:** dihexa acetate was among **12 peptides removed from FDA 503A Category 2** (restricted list) after the original nominator withdrew the petition — removal is NOT approval; it eliminates the explicit citation compounding pharmacies used for blanket refusal.
  * Scheduled for **PCAC review before end of February 2027** alongside LL-37, GHK-Cu, PEG-MGF, Melanotan II.



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## Source & Origin

  * **Developed at:** Washington State University (Joseph Harding lab); spinout M3 Biotechnology → Athira Pharma (founded 2011 by Leen Kawas)
  * **Base compound:** angiotensin IV analog; hexanoic acid N-terminus + aminohexanoic acid linker for metabolic stability
  * **Corporate lineage:** Athira → fosgonimeton failure → oncology pivot → **LeonaBio** (Jan 2026)



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## Sources

1. McCoy AT et al. (2013). "Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents." J Pharmacol Exp Ther 344(1):141–154. PMID 23055539 . Expression of Concern: JPET 378(3):313, 2021, PMID 34551989 . (PubMed 23055539, PubMed 34551989)
2. Benoist 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." JPET . RETRACTED April 2025 (retraction notice: PMC13095468 ). (PMC13095468)
3. Chen Y et al. (2022). "AngIV-Analog Dihexa Rescues Cognitive Impairance and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway." Mol Neurobiol . PMC8615599 (independent replication). (PMC8615599)
4. NCT04488419 (NCT04488419)
5. Ingle PN et al. (2024). LIFT-AD phase 2/3 fosgonimeton trial publication. PMC12701236 . (PMC12701236)
6. NCT04491006 (NCT04491006)
7. NCT04831281 (NCT04831281)