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.
Summary drafted from this entry’s sources; editorial review pending.
01Key questions
Has dihexa been tested in humans?
No. There are no published human studies and none registered on ClinicalTrials.gov; the closest class data is the failed fosgonimeton program in Alzheimer's.
Does dihexa work?
Unknown, and the preclinical basis is damaged: the foundational McCoy 2013 paper is under an expression of concern and the Benoist 2014 mechanism paper was retracted in April 2025. One independent mouse study is supportive.112
Is dihexa safe?
There is no long-term safety data in any species. It activates HGF/c-Met, a pro-cancer signaling axis, and has a ~12-day half-life in rats; the entry calls it not recommended outside trials.
Is dihexa legal in the US?
It is not FDA-approved. It was removed from the 503A Category 2 list in April 2026 after the nominating petition was withdrawn, and is scheduled for PCAC review by February 2027.2
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
02Overview
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.
03Research 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) — foundational procognitive/aged-rat paper | Expression of Concern | 2021 (JPET 378(3):313; PMID 34551989) |
| Benoist et al. 2014 — HGF/c-Met dependence of synaptogenesis (the mechanism paper) | RETRACTED | April 2025 (retraction notice PMC13095468) |
| Kawas et al. 2012 — AngIV analog development | RETRACTED | April 2025 |
| Four JPET papers from Wright/Harding lab overall | Formal expressions of concern | 2021 |
Swipe table →
- 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.
04Mechanism 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)
- Synaptogenesis — new functional synapses
- Dendritic arborization
- Spinogenesis — the famous "~3-fold spine increase" figure (McCoy 2013: ~15 → ~41 spines/50 µm dendrite) comes from the paper under expression of concern
- 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.
05Primary 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 (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 |
Swipe table →
06Clinical 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, 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 |
| ACT-AD (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) | 40/70 mg | Terminated Dec 2022 at 28/75 enrolled |
Swipe table →
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.
07Uses
⚠️ 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
08Safety 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 |
Swipe table →
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.
09Regulatory 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.
10Source & 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)
11Where to get it
Dihexa is sold mainly through gray-market vendors whose products are not independently tested. We don't link to sellers of compounds like this, affiliate or otherwise. How we make money
12Connections
13Sources
- 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
- 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
- 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
- NCT04488419NCT04488419
- Ingle PN et al. (2024). LIFT-AD phase 2/3 fosgonimeton trial publication. PMC12701236 .PMC12701236
- NCT04491006NCT04491006
- NCT04831281NCT04831281
14Entry history
Latest content update.
Heretic informs and never prescribes. Where amounts appear, they describe what published studies used. Talk to a qualified clinician before acting on anything here.