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Cognitive

All peptides
HGF / c-Met agonist (cognitive)

Dihexa

Also known as: Dihexa acetate, N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, PNB-0408, Hexanoyl-Tyr-Ile-Aha

Animal-only peptide aimed at restoring brain connections, with replicated cognitive-recovery signals in rodent models of Alzheimer's disease. No human trials.

Reviewed 2026-05-05

What it does

Dihexa is a small synthetic peptide designed to enhance signaling between brain cells, with the explicit goal of promoting new connections (synaptogenesis) and rescuing cognitive function in animal models of Alzheimer's disease. Rodent studies report improved memory performance and reduced disease-related brain pathology. There are no completed published human trials at any phase. Community framing as a general-purpose nootropic for healthy adults runs well past what the animal data supports — the rodent work was specifically in cognitively-impaired animals, not normal ones.

Used for

Dose

Starting
10,000 mcg · once daily
Common
27,500 mcg · once daily
Upper
45,000 mcg · once daily
When
MorningWakefulness-promoting via HGF-system upregulation in animal data. No human chronopharmacology yet, but the alertness signal favors morning timing.
Site
oral or sublingual (community use, no human PK data)

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⚠ Caution

  • Any active or prior malignancy (HGF/c-Met signaling drives tumor invasion in many cancer types — this is a real, mechanistic safety concern, not theoretical)
  • Family history of c-Met-driven cancers (gastric, certain lung, hepatocellular)
  • Pregnancy and breastfeeding
  • Use during chemotherapy or immunotherapy (interaction with cancer biology unknown)
  • Known hypersensitivity

Your stack

Track this peptide in your protocol — dose, schedule, vials on hand, refill projection. Stays in your browser; no account needed.

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Use this peptide

Reconstitution & storage

Most community use is oral or sublingual — no reconstitution. The hexanoyl modification was designed for oral bioavailability and BBB penetration; vendor preparations vary in quality.

Storage. Vendor-dependent. Powder forms typically refrigerated; oral capsules at room temperature, dry, protected from light.

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Monitoring & questions

Reported side effects
  • Unknown in humans — no published human safety data
  • Theoretical: tumor promotion via c-Met signaling (the most serious uncharacterized risk)
  • Theoretical: off-target effects on systemic c-Met-expressing tissues (liver, kidney, vascular endothelium)
  • Anecdotal community reports: headache, anxiety, sleep disturbance — uncontrolled
Biomarkers Juno tracks

Reference

How it works

Acts as a positive allosteric modulator / mimetic of hepatocyte growth factor (HGF) at its receptor c-Met (MET). c-Met activation drives PI3K/AKT and MAPK signaling and, in central neurons, can promote dendritic spine formation and synaptogenesis. Sun 2021 specifically traced the procognitive effect in APP/PS1 mice through PI3K/AKT activation, with the PI3K inhibitor wortmannin reversing the anti-inflammatory and anti-apoptotic effects. The mechanism framing is broadly supported by the wider c-Met / HGF literature; dihexa-specific mechanism claims that originated solely from the Wright/Harding/Kawas lab during 2008-2014 should be treated cautiously given the documented integrity findings on that lab's output. The proposed safety concern is not theoretical: HGF/c-Met signaling is a known oncogenic driver in multiple epithelial cancers (gastric, certain lung, hepatocellular), and any chronic systemic c-Met agonist carries that risk profile.

Juno's take

The animal cognition signal is real, but two things complicate it. The foundational lab work behind the original mechanism story has a documented data-integrity finding — a federal settlement, fabricated images, one paper formally retracted. The cleanest independent rodent replication came from an unrelated group. Zero human trials. And the receptor target is a known cancer driver — active or prior malignancy is a hard contraindication, not theoretical.

EvidenceTier 3 — Animal / in vitro

Tiers are per indication. The same molecule can be Tier 1 for one use and Tier 4 for another — the tier reflects published literature, not community framing.

Cognitive function in Alzheimer's-disease animal models (preclinical)

Tier 3medium confidence

Replicated rodent cognitive-recovery signal across labs and disease models. Anchor evidence is Sun 2021 (China Pharmaceutical University / Nanjing Medical University; no overlap with the originating Wright/Harding lab) — APP/PS1 transgenic AD mice, restored Morris water-maze performance, increased neuronal cell counts and synaptophysin, reduced neuroinflammation, all reversed by PI3K inhibition. Editorial caveat that does not vanish: foundational mechanistic work from the Wright/Harding lab between 2008-2014 is entangled with a $4M DOJ Athira False Claims Act settlement (Jan 2025) and one formal retraction (Benoist 2014, April 2025). Tier 3 reflects 'strong preclinical only' on the Sun 2021 anchor + class-level c-Met mechanism + the broader AngIV-class systematic review (Ho & Nation 2018), with the integrity caveat held openly in the reviewer notes rather than buried.

Sun X et al. 2021Ho JK et al. 2018U.S. Department of Justice et al. 2025Benoist CC et al. 2014

Alzheimer's disease in humans

Tier 4high confidence

No completed published human trial of any phase. The Alzheimer's Drug Discovery Foundation's Cognitive Vitality assessment notes the absence of human trial data and characterizes dihexa as an experimental compound requiring substantial additional research before clinical validation. Community marketing as an AD intervention is not supported by clinical evidence.

Alzheimer's Drug Discovery Foundation et al. 2021

Cognitive enhancement in healthy adults (nootropic)

Tier 4high confidence

Mechanistic extrapolation from animal disease models. Rodent studies were specifically in cognitively-impaired animals (scopolamine, aged, transgenic AD); enhancement in cognitively-normal humans is a distinct claim with zero supporting evidence.

No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.

Peripheral nerve regeneration

Tier 4medium confidence

Weiss 2021 reported improved limb-function recovery in a rat sciatic-nerve damage-repair model. Single preclinical study with overlapping lab provenance to the Wright/Harding group; no human evidence; tainted-by-association concern given the documented integrity findings on the wider dihexa-specific literature from that lab orbit.

Weiss JB et al. 2021
Citations (7)
  1. [1]
    AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway
    Sun X, Deng Y, Fu X, Wang S, Duan R, Zhang Y, et al. · Brain Sciences · 2021 · PMID 34827486
    Genuine independent rodent replication (China Pharmaceutical University / Nanjing Medical University; no overlap with the Wright/Harding/Kawas lab). Transgenic APP/PS1 model, PI3K/AKT mechanism trace. The strongest single piece of dihexa-specific preclinical evidence not entangled with the Athira fraud history. Anchor for the Tier 3 preclinical-AD-cognition indication.
    View source
  2. [2]
    Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies
    Ho JK, Nation DA · Neuroscience & Biobehavioral Reviews · 2018 · PMID 29733881
    Systematic review of 32 animal studies establishing the class-level cognitive signal for angiotensin IV and analogs. Class-level support for the Tier 3 preclinical indication; not a dihexa-specific replication.
    View source
  3. [3]
    Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies
    Weiss JB, Phillips CJ, Malin EW, Gorantla VS, Harding JW, Salgar SK · Annals of Medicine and Surgery (Lond) · 2021
    Single-lab rat model on peripheral nerve regeneration. Includes Harding (the dihexa originating-lab senior author) — partial overlap with the lab orbit that produced the fraud-tainted work, so cited with that caveat.
    View source
  4. [4]
    Dihexa — Cognitive Vitality assessment
    Alzheimer's Drug Discovery Foundation · ADDF Cognitive Vitality (alzdiscovery.org) · 2021
    Independent expert assessment confirming the absence of human trial data and characterizing dihexa as preclinical-only. Anchors the Tier 4 framing for the human-applicable indications.
    View source
  5. [5]
    Athira Pharma Inc. Agrees to Pay $4M to Settle False Claims Act Allegations Related to Scientific Research Misconduct
    U.S. Department of Justice, Office of Public Affairs · DOJ press release · 2025
    Documents the January 2025 $4M settlement and the underlying admission by former Athira CEO Leen Kawas of systematic image manipulation between 2008-2012 in dihexa-supporting research. The single most important editorial-context citation for this entry.
    View source
  6. [6]
    The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system — RETRACTED 2025
    Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW (RETRACTED) · Journal of Pharmacology and Experimental Therapeutics · 2014
    Cited as a record of the retracted foundational mechanistic paper, NOT as supporting evidence. Retracted April 2025 following image-manipulation investigation tied to the Athira / Kawas DOJ settlement. Listed here so the editorial context is visible; should never be used to support an indication tier.
    View source
  7. [7]
    FDA Announces Removal of 12 Peptides from 503A Category 2 and Schedules PCAC Meetings
    U.S. Food and Drug Administration / PCAC · FDA notice / industry coverage (Frier Levitt, Orrick, RAPS) · 2026
    Documents the April 15, 2026 removal of dihexa acetate (plus 11 other peptides) from 503A Category 2 and the PCAC review schedule. Anchors the fda_status field. NOT evidence of safety or efficacy — just regulatory scheduling.
    View source