Class · Neurological & cognitive · Synthetic angiotensin IV analog · proposed HGF/c-Met modulator · experimental nootropic-neurotrophic
Dihexathe angiotensin IV analog · experimental, preclinical-only, no validated human dose
Dihexa (also called PNB-0408) is an experimental brain-research compound built from a piece of the body's angiotensin system. In animals it is studied for whether it can help neurons form new connections and improve memory. It is the near-opposite of an approved drug like tesamorelin: it has no FDA approval, no established human dose, no completed human trials, and no validated safety program. All of the encouraging data come from rats and mice, and an independent review flagged a theoretical cancer-related concern and the absence of any long-term safety data. Adding to the uncertainty, the single most-cited paper explaining how Dihexa was supposed to work was formally retracted in 2025 for falsified data. Everything on this page is a research model, not patient instructions.
Dihexa (PNB-0408 / ATH-1001; N-hexanoic-Tyr-Ile-(6) aminohexanoic amide; C₂₇H₄₄N₄O₅, MW 504.7 Da) is a metabolically stabilized, orally active, blood-brain-barrier-permeable angiotensin IV analog investigated as a procognitive / synaptogenic agent. Its most informative in-vivo study, in APP/PS1 Alzheimer-model mice, reported restored Morris-water-maze learning, increased synaptophysin and neuronal counts, reduced glial inflammation, and PI3K/AKT activation reversed by wortmannin. The proposed HGF/c-Met mechanism rests heavily on a 2014 paper retracted in April 2025 for fabricated data, so the central mechanism is best read as plausible-but-unproven. There is no human efficacy or safety trial, no human PK, and no validated biomarker model; the dominant clinical caution is mechanism-derived oncologic risk from chronic HGF/MET activation.
Dihexa (CAS 1401708-83-5, PubChem CID 129010512, UNII 9WYX65A5C2, C₂₇H₄₄N₄O₅, 504.7 g/mol) is a hexanoyl-capped Tyr-Ile-aminohexanoic-amide angiotensin IV analog engineered for metabolic stability and CNS penetration. Secondary pharmacology summaries describe high-affinity HGF binding (reported Kd ≈ 65 pM) and an in-vitro neurotrophic potency cited as ~7 orders of magnitude greater than BDNF — an assay-specific, non-clinical metric. The replicated in-vivo signal in APP/PS1 mice implicates a brain AngIV → PI3K/AKT axis (wortmannin-reversible) with synaptophysin upregulation, anti-inflammatory cytokine shift, and anti-apoptotic effects, while the originally proposed HGF/c-Met-dimerization mechanism is compromised by the April-2025 retraction of its foundational paper. Overall GRADE for human use: VERY LOW — preclinical evidence only.
0Completed human efficacy/safety trials located
504.7 DaC₂₇H₄₄N₄O₅ · CAS 1401708-83-5 · CID 129010512
Not named · likely S0 (non-approved) · high caution
01 · At a glance
Key facts & headline data.
The facts that define Dihexa's position in this atlas — a high-interest but low-human-evidence molecule. Everything here is preclinical or regulatory; there is no approved indication, no human dose, and no validated safety program, and the central mechanism story is complicated by a 2025 retraction. Read the grades literally: P = animal/preclinical, C = mechanistic review, D = regulatory/expert, and there is no Grade A or B anywhere on this page.
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Origin · development
WSU → M3 → Athira
Developed out of the Washington State University angiotensin IV analog program (Harding/Wright) as a metabolically stabilized, BBB-permeable AngIV analog. Commercial development passed through M3 Biotechnology, later Athira Pharma; Dihexa carries the code ATH-1001.
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Primary research use
Cognitive / AD models
Investigated mainly in animal models of cognitive impairment and Alzheimer-like pathology — restored spatial learning and synaptic markers in APP/PS1 mice. No approved human indication; no completed human efficacy trial located.
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Mechanism headline
HGF/MET — retracted source
Designed to potentiate HGF/c-Met signaling, but the foundational 2014 mechanism paper was retracted in April 2025 for falsified/fabricated data. The better-supported in-vivo signal is a brain AngIV → PI3K/AKT axis. Treat the mechanism as plausible but not secure.
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Potency claim
Kd ≈ 65 pM · ~10⁷× BDNF
Secondary pharmacology summaries cite high-affinity HGF binding (~65 pM) and ~seven orders of magnitude greater neurotrophic potency than BDNF in vitro. This is an assay-specific, non-peer-reviewed metric — not a clinical efficacy figure.
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Dose status
No human dose
No human dose, PK, or cycle is established. Animal exposure anchors are oral 1.44–2.88 mg/kg in APP/PS1 mice and ~2 mg/kg/day oral in rat cognitive models, with lab i.p./i.v./i.c.v. routes summarized separately. Animal anchors are not human protocols.
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Regulatory status (May 2026)
Not approved · Category 2
Not FDA-approved for any indication; Dihexa-related material has appeared in FDA peptide-compounding Category-2 (significant-safety-risk) discussions, which is a risk flag, not an approval. For tested athletes, treat as likely-prohibited under WADA S0 (non-approved substances).
02 · Mechanism of action
How an AngIV analog may work.
Dihexa is built from a fragment of the brain's own angiotensin system. The idea is that it helps neurons build and repair the connections (synapses) that memory depends on. The original story was that it does this by boosting a growth signal called HGF and its switch, c-Met — but the key paper behind that story was retracted in 2025, so scientists are no longer sure that is the real mechanism. What animal studies more reliably show is that Dihexa switches on a cell-survival pathway (PI3K/AKT), increases synapse markers, and calms inflammation in the brain — all in mice and rats, never yet in people.
Six linked mechanistic arms, all preclinical. First — the proposed HGF/c-Met-potentiation mechanism, now compromised by the April-2025 retraction of its foundational paper for fabricated data. Second — synaptogenesis: increased synaptophysin and neuronal counts in APP/PS1 mice. Third — PI3K/AKT survival signaling, with anti-inflammatory and anti-apoptotic effects reversed by wortmannin. Fifth — anti-inflammatory glial modulation (↓IL-1β/TNF-α, ↑IL-10). Fourth — the brain renin-angiotensin / AngIV axis as the research lineage. Sixth — the broader neurotrophic-mimetic strategy, conceptually promising but hard to translate.
Dihexa is best modeled as a brain-RAS-derived agent acting through a PI3K/AKT-centered survival-and-plasticity program, with the originally proposed HGF/c-Met dimerization mechanism now evidentiarily compromised. The replicated APP/PS1 dataset shows wortmannin-reversible PI3K/AKT activation, synaptophysin upregulation, Nissl-defined neuronal preservation, glial deactivation, and a pro-resolution cytokine shift. The HGF/MET pathway invoked for synaptogenesis is the same pathway central to oncogenic growth, motility, and invasion — the mechanistic basis for the page's oncologic caution. Net mechanistic confidence: hypothesis-grade; no human confirmation exists.
D
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HGF / c-Met modulation · retracted source
The original headline mechanism. Dihexa was proposed to bind HGF and potentiate HGF-dependent c-Met phosphorylation, producing synaptogenic and neurite/spine effects. The 2014 paper that established this HGF/c-Met dependence was formally retracted in April 2025 after a Washington State University investigation found falsified/fabricated data, with two authors held responsible. Treat this pathway as plausible but not securely demonstrated.
⚠ Retracted-evidence caution
The foundational HGF/c-Met synaptogenesis paper is retracted (notice J Pharmacol Exp Ther 2025;392(4):103567); it must not be used as clean mechanistic proof, and downstream claims that rely on it inherit that uncertainty.
Clinical significance: Because the mechanism is unsettled, any "HGF-mimetic" framing for Dihexa should be presented cautiously. Independent HGF/MET literature supports the pathway's general procognitive plausibility, but does not rehabilitate the specific retracted Dihexa data.
Molecular detail: HGF/c-Met is a receptor-tyrosine-kinase system linked to neurogenesis, angiogenesis and synaptogenesis; the proposed model had Dihexa acting as an HGF-dimerization mimetic to enhance MET activation. A high-affinity HGF interaction (reported Kd ≈ 65 pM) is cited in secondary sources but is assay-specific.
P
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Synaptogenesis · dendritic spine formation
The central claim is that Dihexa increases the number or function of neuron-to-neuron connections. In APP/PS1 mice, Dihexa increased synaptophysin (SYP) protein and neuronal-cell counts by Nissl staining alongside improved Morris-water-maze performance — a coherent structure-plus-behavior signal, but in a single rodent model.
Clinical significance: Synaptophysin and spine density are mechanistically appealing surrogates for "plasticity," but none are validated as Dihexa response markers in humans. The behavioral readouts (water maze) do not translate directly to human cognition.
Molecular detail: Readouts include synaptophysin/SYP expression, Nissl-defined neuronal preservation, and hippocampal-circuit-dependent spatial memory. The originally reported spine-density mechanism overlapped with the now-retracted HGF/c-Met dataset, so weight it accordingly.
P
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PI3K / AKT survival signaling
The best-supported in-vivo arm. In APP/PS1 mice Dihexa increased PI3K and phospho-AKT; the PI3K inhibitor wortmannin reversed its anti-inflammatory and anti-apoptotic effects — a pharmacological loss-of-function that ties the benefits to PI3K/AKT. This is the cleanest mechanistic evidence on the page.
Clinical significance: PI3K/AKT governs neuronal survival, apoptosis resistance, and plasticity. It is also a broadly pro-growth pathway, which feeds the same oncologic-caution theme that runs through Dihexa's safety profile.
Molecular detail: The wortmannin-reversal design specifically implicates the PI3K/AKT axis downstream of the brain AngIV signal, linking it to reduced glial activation, lower IL-1β/TNF-α, and higher IL-10.
C
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Brain renin-angiotensin · AngIV axis
Dihexa belongs to a family of brain angiotensin peptides linked to memory in animal models. It is a metabolically stabilized AngIV analog from the brain-RAS / AT4-IRAP cognition field. A systematic review found AngIV and analogs improved performance across many animal cognitive-deficit models.
Clinical significance: The AngIV lineage is well-established as a research line, not as a human therapy. Its value here is contextual — it explains why Dihexa was built and where the cognitive hypotheses come from.
Molecular detail: The AT4 / IRAP (insulin-regulated aminopeptidase) axis and brain RAS overlap with memory consolidation; AngIV's short half-life and poor BBB penetration motivated stabilized analogs like Dihexa.
P
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Anti-inflammatory · glial modulation
In Alzheimer-like mice Dihexa reduced neuroinflammatory markers. It decreased astrocyte and microglial activation, lowered the pro-inflammatory cytokines IL-1β and TNF-α, and raised the anti-inflammatory cytokine IL-10 in APP/PS1 mouse brain.
Clinical significance: Neuroinflammation is a plausible therapeutic target in neurodegeneration, but these are animal cytokine endpoints with no validated human monitoring counterpart for Dihexa.
Molecular detail: The cytokine shift was wortmannin-sensitive, placing it downstream of PI3K/AKT, and accompanied reduced glial activation and anti-apoptotic effects.
Dihexa fits a broader strategy of using small molecules to mimic or amplify neurotrophic growth-factor signaling. This matters because full growth factors struggle with BBB penetration, delivery, and short in-vivo duration — the gap small-molecule mimetics are designed to fill.
Clinical significance: The concept is established; Dihexa-specific clinical translation is not. The class as a whole (TBI, Parkinson-like, synaptic-repair settings) has struggled to move from preclinical promise to human benefit.
Molecular detail: Growth-factor mimetics aim to reproduce HGF/MET- or neurotrophin-like signaling with drug-like PK; reviews flag delivery, safety, and BBB challenges as the central translation barriers.
Research dosing architecture — not a clinical protocol.
This is the core of the engine, and for Dihexa it must be read carefully. Dihexa is the opposite of an approved drug: there is no approved dose, no validated human dosing, PK, safety, cycle length, or biomarker model. Every value below is a research model built from animal-study exposure ranges and non-validated practice-pattern placeholders, organized into the same skeleton used elsewhere in the atlas — evidence basis, starting anchor, dose ladder, maintenance, cycle, reconstitution math, monitoring overlay, and explicit grade — purely so the structure is comparable. None of it constitutes patient instructions. The working unit is milligrams (mg), with µg conversion in the calculator. The highest grade anywhere in this section is P (preclinical/animal).
Important · no approved dose exists
Dihexa has no FDA-approved indication, no established human dose, no validated human PK or safety program, and no validated biomarker-monitoring model. The numbers below are animal-literature anchors and practice-pattern placeholders for page-modeling only, expressed in the engine's standard format. Oral animal anchors come from APP/PS1 mouse arms (1.44 and 2.88 mg/kg) and rat cognitive models (~2 mg/kg/day), with i.p./i.v./i.c.v. exposures summarized as laboratory routes only. They must not be presented as, or converted into, human dosing instructions.
PK note · why there is nothing to titrate
No reliable human Cmax, Tmax, clearance, bioavailability, or half-life has been established. Animal work describes Dihexa as orally active and able to cross the blood-brain barrier, and secondary sources describe it as metabolically stabilized / relatively long-lived versus parent AngIV analogs, but there is no validated human PK profile and therefore no peak/trough or steady-state concept to titrate against. Any "dose response" claim for Dihexa is, at present, an extrapolation from rodent exposure.
Oral Animal-Research Model
Oral · rodent exposure anchors 1.44–2.88 mg/kg · finite study windows · NOT a human dose
Grade P
Evidence basis
APP/PS1 Alzheimer-model mouse study using oral Dihexa and aged / scopolamine-impaired rat cognitive models (~2 mg/kg/day oral). The McCoy rat work carries a 2021 Notice of Concern — interpret cautiously.
Starting "dose"
No human starting dose exists. Animal reference anchor: 1.44 mg/kg → 2.0 mg/kg/day → 2.88 mg/kg oral exposure. These are mouse/rat exposures, not human doses, and must not be scaled to a person as an instruction.
Dose ladder (animal)
Low 1.44 mg/kg and high 2.88 mg/kg (APP/PS1 mice); standard anchor 2.0 mg/kg/day (rat oral cognitive model). Store this as animal_exposure_basis, never human_dose_recommendation.
Maintenance / cycle
Not established. Animal studies used finite experimental windows; use study duration only when building research tables. No washout is defined.
Reconstitution / formulation
Oral solutions are not standardized. The calculator below produces mass-per-dose reconstitution math only (for an injectable-style mg/mL model), not an oral clinical direction.
Monitoring overlay
No validated Dihexa monitoring exists. Optional research markers only: cognition scales (MoCA/MMSE-like), sleep, anxiety, BP/HR, inflammatory labs, liver/kidney panels, and a cancer-history screen. All unvalidated for this compound.
Translation caution
Human oral bioavailability and drug interactions are unknown; no human PK exists. Animal-to-human conversion should not be auto-displayed as a clinical instruction.
⚠ Research model only
Avoid any human-claim language. The same HGF/MET pathway Dihexa is meant to engage is central to tumor biology — chronic growth-factor-pathway activation is the dominant theoretical risk, and a personal cancer history is a hard-stop consideration.
SC / topical · commonly discussed in peptide-practice settings · no robust human evidence
Grade D/P
Evidence basis
Routes such as oral, topical/transdermal, and subcutaneous are discussed in peptide-practice settings, but are not supported by robust published Dihexa human trials. This panel exists only to keep the engine structure complete.
Starting dose
Not established. Do not display as a recommended dose. There is no validated SC/transdermal dose for Dihexa in humans.
Dose ladder / maintenance / cycle / washout
Not established on any axis. Any specific SC numbers circulating in the practice community are unsourced placeholders.
Reconstitution
If modeled as an injectable, the calculator's mg/mL math applies mechanically — but with the explicit caveat that there is no validated SC absorption, dose, or endpoint for Dihexa.
Monitoring overlay
Same global safety grid as elsewhere; every marker is unvalidated for Dihexa.
⚠ Major evidence gap
No validated human absorption, safety, sterility, or clinical-endpoint evidence exists for SC or transdermal Dihexa. Any injectable non-approved peptide also carries sterility, impurity, aggregation, and excipient risk.
Intraperitoneal · Animal Laboratory Route
i.p. · preclinical only · up to 20 mg/kg in rats · not a human route
Grade P
Evidence basis
Preclinical laboratory route only.
Dose ladder (animal)
Secondary evidence summaries report i.p. testing up to 20 mg/kg in rats. Not clinically applicable.
Maintenance / cycle / washout
Not established — study-specific only.
Monitoring overlay
Animal-behavior endpoints, toxicity observation, body weight, organ histology where applicable.
⚠ Animal-route only
Intraperitoneal dosing is not a human clinical route and must not appear on a consumer-facing protocol card except as "animal-route only."
Intravenous · Animal Laboratory Route
i.v. · preclinical only · up to 10 mg/kg in rats · no human IV model
Grade P
Evidence basis
Preclinical exposure route in secondary summaries.
Dose ladder (animal)
Secondary summaries report i.v. testing up to 10 mg/kg in rats, while noting no human dose is established.
⚠ Not for protocol display
Intracerebroventricular dosing is unsuitable for any clinical-protocol display; it belongs only in the evidence-base grid.
Global dose bands · animal-literature anchors (NOT human)
Animal exposure tiers & laboratory-route ceiling.
These are animal-literature anchors, not human protocols. They are stored as animal_exposure_basis and shown in the engine's standard band format for structural parity only. Animal-to-human conversion must not be auto-displayed as a clinical instruction.
Band
Animal-study anchor
Exposure
Basis
Grade
Low
APP/PS1 mouse low arm
1.44 mg/kg
Mouse cognitive / inflammation model
P
Standard
Aged / scopolamine rat oral
2.0 mg/kg/day
Oral rat cognitive model (2021 Notice of Concern)
P
High
APP/PS1 mouse high arm
2.88 mg/kg
Mouse cognitive / inflammation model
P
Upper lab-route
i.v. / i.p. summary
i.v. ≤10 · i.p. ≤20 mg/kg
Non-oral preclinical route summary
P/D
Weight-band interpolation — animal-equivalent exposure math only
⚠ Not for human dosing. This table mechanically multiplies the animal mg/kg anchors by body weight for calculator logic and structural parity. It does not represent a recommended human dose and must never be read as one.
Body weight
Low ×1.44 mg/kg
Standard ×2.0 mg/kg
High ×2.88 mg/kg
55 kg
79.2 mg
110 mg
158.4 mg
65 kg
93.6 mg
130 mg
187.2 mg
75 kg
108 mg
150 mg
216 mg
85 kg
122.4 mg
170 mg
244.8 mg
95 kg
136.8 mg
190 mg
273.6 mg
105 kg
151.2 mg
210 mg
302.4 mg
These figures are direct mg/kg×weight products of rodent exposures and are physiologically meaningless as human doses — interspecies scaling (e.g. allometric / HED conversion) would reduce them substantially and still would not yield a validated human dose, because none exists. Shown only for engine parity and clearly labeled as animal-equivalent.
Decision logic · research-model hold/stop rules
Hold, hard-stop & contraindication logic.
Because there is no validated efficacy criterion, Dihexa "titration" is really a set of do-not-proceed / hold / hard-stop rules dominated by the mechanism-derived oncologic caution. All rows are grade D research-model logic, not clinical guidance.
Trigger
Action
Rationale
Grade
Active cancer · unexplained mass · high-risk premalignant condition
Hard stop — contraindication
HGF/MET drives growth, motility, invasion and survival in cancer biology.
P/D
Pregnancy · breastfeeding · minors
Hard stop
No reproductive/developmental safety data.
D
No baseline / no validated endpoint
Do not claim a protocol response; research endpoint only
No validated clinical response criterion exists.
D
New anxiety, insomnia, agitation, headache, BP change
Hold
CNS-active growth-factor modulation has unknown human tolerability.
None of these are validated for Dihexa response monitoring. The bundle is an exploratory research scaffold only, shown for structural parity with validated-biomarker pages.
Endpoint
Why it might be considered
Timing
Validated?
Cancer-history screen
Mechanism-derived oncologic caution (HGF/MET)
Before any research-model use
⚠ Hard-stop gate
MoCA / MMSE / computerized cognition
Tracks cognitive domains
Baseline + interval
❌ Exploratory
Sleep / insomnia log
CNS tolerability
Weekly
❌ No
BP / HR
General physiologic safety
Baseline + periodic
❌ No
CBC w/diff · CMP (AST/ALT, bilirubin, eGFR)
General safety; unknown metabolism/clearance
Baseline + periodic
❌ No
hs-CRP · IL-1β / TNF-α / IL-10
Animal-study cytokine relevance
Research-only
❌ Research-only
IGF-1
Growth-signaling context (not mechanism-specific)
Optional
❌ Exploratory caution
Tumor markers
Not recommended as broad screening; may mislead
Only if clinically indicated
⚠ Avoid unless indicated
No biomarker is validated for tracking Dihexa response; cognitive scales in particular are not validated for this compound. The only non-negotiable item is the up-front cancer-history gate, derived from HGF/MET biology rather than from a Dihexa adverse-event signal.
Research-model timeline · structural parity only
Visual model: screen → research window → reassess.
GateSTOP?cancer-history screenActive/recent malignancy, mass, premalignant = hard stop
Baseline0endpoints onlyDefine research endpoints; no response claim
Windowanimalanchor onlyFinite study-style window · no validated human dose
Any AEHOLDtolerabilityNew CNS/mood/BP signals → hold
Reassess↺no escalationNo escalation on subjective benefit alone
Red flagsSTOPhardWorsening cognition/mood/neuro → hard stop
L2 · Reconstitution & dose math (research model)
Reconstitution & Dose Calculator
Reconstitution math only — not medical dosing advice and not a recommended human dose. Dihexa has no validated human dose; this tool simply computes mg/mL concentration and draw volume for a chosen vial/water/target combination so the page mirrors the rest of the atlas. Verify purity, sterility, endotoxin, identity, and storage, and use only product from a licensed / verified source for any injection.
Concentration
—
Draw volume
—
Units (U-100)
—
Doses per vial
—
Basis
—
04 · Combination protocols
Stacking Dihexa — speculation only.
No human combination data exist for Dihexa. Every pairing below is a mechanistic or practice-pattern idea, not a validated protocol, and the defining engine rule is mechanism-derived: do not stack Dihexa with any other experimental growth-factor, angiogenic, or proliferative-signaling agent in anyone with active malignancy, recent cancer treatment, unexplained masses, high-risk premalignant disease, or strong cancer-risk concern. The single best-supported "stack" is not a drug at all — it is a structured cognitive-endpoint framework to test whether the synaptic claims translate.
The most defensible pairing is methodological, not pharmacological: combine any Dihexa research use with a structured, pre-specified cognitive-endpoint framework so the synaptic/plasticity claims can actually be tested rather than assumed. No clinical validation exists, and performance claims should be avoided — but this is the only "combination" that improves the evidence rather than compounding the uncertainty.
Commonly discussed nootropic-peptide pairing with distinct proposed mechanisms — neuropeptide/BDNF-related modulation (Semax/Selank) versus Dihexa's AngIV/HGF-MET hypothesis. No human combination safety data exist, and stacking two CNS-active experimental agents multiplies unknown tolerability and interaction risk. Speculative only.
Practice-pattern rationale is to support cellular energetics while targeting plasticity. There is no Dihexa-specific evidence for this combination; it rests entirely on general "support metabolism + plasticity" reasoning, not on data showing the pairing changes any Dihexa outcome.
Component
Role
Status
Dihexa
Plasticity / survival signaling (hypothesis)
Preclinical (P)
NAD⁺ support
Cellular-energy framing
No Dihexa-specific data (D)
Dihexa + GLP-1 · metabolic-cognitive model
Conceptual
Dihexa (research model)GLP-1 agonistmetabolic-cognitive link
A conceptual link between metabolic health and cognition motivates this pairing, but there is no Dihexa-specific combination evidence and additive GI/CNS effects are unknown. Conceptual only; avoid claims.
Component
Role
Status
Dihexa
Cognitive hypothesis
Preclinical (P)
GLP-1 agonist
Metabolic-cognitive framing
No Dihexa-specific data (D/P)
Hard constraint
⛔ Mechanism-derived oncologic hard stop. Because HGF/MET is a central growth, motility, invasion and survival pathway in cancer biology, Dihexa should not be stacked with other experimental growth-factor, angiogenic, or proliferative-signaling agents in anyone with active malignancy, recent cancer treatment, unexplained masses, high-risk premalignant disease, or strong cancer-risk concern. This is a conservative, mechanism-based caution, not a proven Dihexa adverse-event signal — but with no human safety data to reassure against it, it functions as a hard stop. Avoid stacking CNS-active experimental agents generally, given the complete absence of human combination tolerability data.
05 · Safety profile & contraindications
Mostly theoretical — because there is no human dataset.
Dihexa's safety base is the inverse of a well-characterized drug: no robust human adverse-event dataset exists; the profile is built from animal/preclinical observation plus theoretical mechanism concerns, and an independent review specifically highlights the absence of long-term safety studies and a theoretical tumorigenesis / cancer-progression concern through HGF/c-Met activation. The dominant, recurring caution is oncologic, and it flows from mechanism — not from an observed signal in people, because there is no people-level signal to observe.
Observed Data (preclinical only — no human AE dataset)
No human adverse-event dataNo robust human safety dataset was located; the evidence base is animal/preclinical plus theoretical mechanism concerns.
Animal tolerability (limited)Rodent cognitive/inflammation studies reported benefit at oral 1.44–2.88 mg/kg without emphasizing overt toxicity, but used finite windows and small n.
CNS tolerability (unknown)Unknown human CNS effects; possible anxiety, insomnia, agitation, or mood changes from a CNS-active growth-factor modulator.
Cancer progression / tumorigenesisHGF/MET is a known growth, motility, invasion and survival pathway in cancer biology — the dominant theoretical risk of chronic activation.
Angiogenesis / tissue remodelingGrowth-factor-pathway modulation may affect abnormal tissue remodeling and neovascularization.
Neuropsychiatric effectsUnknown human CNS effects; possible anxiety, insomnia, agitation, mood changes.
Interaction riskNo interaction map with stimulants, antidepressants, antipsychotics, GLP-1s, hormones, or other nootropics.
Reproductive / developmentalNo pregnancy, lactation, or developmental safety data — absolute avoid.
Evidence-integrity riskThe foundational mechanism paper was retracted for fabricated data, so even the mechanistic basis for predicting effects (and risks) is partly compromised.
Contraindication reference
These are precautionary, mechanism-derived contraindications — there is no FDA label to draw from. They are framed conservatively precisely because human safety data are absent.
New malignancy or mass, pregnancy, worsening cognition/mood/neurologic symptoms, or any concern about proliferative signaling. Stop and seek clinician review.
06 · Key studies & research program
A preclinical record — and a retraction.
Dihexa's evidence base is among the thinnest in this atlas for human use: no published human efficacy or safety trial was located, and secondary summaries explicitly state no human studies had been published as of review. The interesting signals are animal-model only — strongest in APP/PS1 mice — and the field is complicated by the April-2025 retraction of the foundational HGF/c-Met mechanism paper. The pivotal record below is therefore an animal record, presented with its integrity caveats intact.
Human trials
0
No completed human Dihexa efficacy/safety trial located. All efficacy evidence is preclinical.
Animal · 2021
APP/PS1
Sun et al. — oral Dihexa rescued spatial learning, raised SYP, activated PI3K/AKT (wortmannin-reversible).
Animal · 2013 ⚠
Rat
McCoy et al. — oral 2 mg/kg/day in aged/scopolamine rats; carries a 2021 Notice of Concern.
Mechanism · 2014 ⚠
RETRACTED
Benoist et al. HGF/c-Met paper — formally retracted April 2025 for fabricated data.
PPreclinical · APP/PS1 mouse · anchor study
Sun et al. 2021 — AngIV-analog Dihexa in APP/PS1 mice (PI3K/AKT)
Oral Dihexa in APP/PS1 Alzheimer-model mice restored Morris-water-maze spatial learning, raised brain AngIV, increased neuronal cells and synaptophysin, reduced astrocyte/microglial activation, lowered IL-1β and TNF-α, raised IL-10, and activated PI3K/AKT — with the anti-inflammatory and anti-apoptotic effects reversed by the PI3K inhibitor wortmannin (Brain Sci 2021;11(11):1487, PMID 34827486). The single most informative in-vivo Dihexa study.
Reported that orally delivered Dihexa (~2 mg/kg/day anchor) restored Morris-water-maze learning in scopolamine-impaired and aged rats and described it as orally active and BBB-permeable (J Pharmacol Exp Ther 2013;344:141-54). This paper carries a 2021 Expression/Notice of Concern and has NOT been formally retracted — read the cognitive-restoration claim with caution.
Benoist et al. 2014 — HGF/c-Met dependence (RETRACTED 2025)
Originally reported that AngIV-derived peptides' procognitive/synaptogenic effects depend on HGF/c-Met activation, with high-affinity HGF binding and c-Met phosphorylation. Formally retracted April 2025 after a Washington State University investigation found falsified/fabricated data; two authors held solely responsible (J Pharmacol Exp Ther 2014;351:390-402; retraction 2025;392:103567). Part of a cluster of Harding-lab / Athira-CEO papers that drew 2021 expressions of concern.
Across many animal cognitive-deficit models, angiotensin IV and analogs (Dihexa's lineage) improved performance, supporting the research rationale while emphasizing experimental-study limitations and the absence of human translation (Neurosci Biobehav Rev 2018, PMID 29733881).
A patent filing in the Dihexa HGF-mimetic lineage includes a 6-OHDA Parkinson-model example dosing oral Dihexa ~2 mg/kg every 48 h with reported motor-deficit reversal. Patent example data (small n, commercial filing) carry low evidentiary weight.
Overall evidence strength for human use: low to very low. Interesting preclinical signals (synaptic markers, PI3K/AKT, inflammatory modulation) sit against an absent human base, a compromised central mechanism, and unknown long-term safety. The biggest missing pieces are human Phase 1 safety, human PK, dose-ranging, a cancer-risk evaluation, neuropsychiatric tolerability, validated biomarkers, and controlled efficacy trials.
Compound
Dihexa
Fosgonimeton (ATH-1017)
Angiotensin IV
Semax
Research frame
Cognitive / synaptogenesis
Alzheimer's / Parkinson's cognition
Memory · brain RAS
Nootropic / neuroprotection
Mechanism class
AngIV analog; HGF/MET hypothesis
HGF/MET positive modulator (prodrug)
Endogenous AngIV / AT4-IRAP
ACTH fragment; BDNF-related
Evidence tier
Preclinical only; no human trials
Human trials exist (distinct compound)
Animal experimental
Human/regional; mixed
Human trials?
❌ None located
✅ Yes (not Dihexa)
❌ No
⚠ Regional/limited
Common route in evidence
Oral (animal)
SC (trials)
ICV / systemic (models)
Intranasal
FDA status
❌ Not approved
❌ Investigational
❌ Not approved
❌ Not approved (US)
Key caveat
⚠ Retracted mechanism paper
Trials don't transfer to Dihexa
Short t½ · poor BBB
Limited rigorous data
Fosgonimeton (ATH-1017) is conceptually related — same HGF/MET neurotrophic space, with genuine human trial history — but it is a distinct compound and its evidence does not transfer to Dihexa (ATH-1001).
Note the distribution: this page contains no Grade A or B references. The strongest evidence is Grade P (animal), and the most-cited mechanism reference (Ref 4) is retracted and is included only to document that retraction — never as support.