Dihexa

What it is

Dihexa is an angiotensin IV-derived synthetic oligopeptide analog studied mainly in preclinical cognition and neurodegeneration models^{[6 –7 ]}. Angiotensin IV-related peptides had been investigated for procognitive effects, but early analogs had major drug-development limitations, including susceptibility to metabolic degradation and poor barrier permeability^{[7 ]}. Dihexa was designed to address those limitations through N- and C-terminal modifications that increased stability and hydrophobicity^{[7 ]}.

The chemical identity most often cited for Dihexa is N-hexanoic-Tyr-Ile-(6) aminohexanoic amide^{[6 –7 ]}. NLM’s MeSH Supplementary Concept record maps the compound to oligopeptides and lists the registry number 9WYX65A5C2^{[6 ]}. The acetate salt appears in FDA compounding materials as “Dihexa acetate”^{[2 ,4 ]}.

The retracted HGF/c-Met mechanism paper

Mechanistically, Dihexa has been promoted as a modulator of hepatocyte growth factor, or HGF, and its receptor c-Met. The strongest early paper supporting that mechanism was the 2014 JPET article by Benoist and colleagues, which reported that Dihexa bound HGF, potentiated HGF/c-Met signaling, and produced synaptogenic and procognitive effects^{[8 ]}. That paper is now formally retracted, and a 2021 notice of concern preceded the retraction^{[9 –10 ]}. As a result, the HGF/c-Met mechanism should be described as a hypothesis with a compromised evidentiary foundation, not as established fact.

Dihexa is commonly discussed in nootropic and peptide communities for cognition, “neuroplasticity,” and dementia. The published evidence does not support clinical use for those purposes. Most evidence is cell-based or animal-based, and FDA states that it has not identified human exposure data for drug products containing Dihexa acetate administered by any route^{[4 ]}.

When used in research, Dihexa has been studied with oral or experimental delivery in animal models^{[7 ,11 –12 ]}. This page does not provide dosing, administration, or sourcing guidance.

Regulatory status

Dihexa is not FDA-approved in the United States for Alzheimer disease, dementia, cognitive enhancement, traumatic brain injury, stroke recovery, Huntington disease, Parkinson disease, anti-aging, nootropic use, or any other indication. No FDA-approved Dihexa prescribing label was identified during this review.

503A — withdrawn nomination, future PCAC consultation

FDA’s 503A framework states that a bulk drug substance used by a state-licensed pharmacy or physician must meet a USP/NF monograph pathway, be a component of an FDA-approved drug product if no monograph exists, or appear on FDA’s 503A bulks list^{[1 ]}. FDA’s April 22, 2026 category document states that Dihexa Acetate was removed from Category 2 because the nomination was withdrawn, but FDA intends to consult the Pharmacy Compounding Advisory Committee before the end of February 2027 regarding potential inclusion of Dihexa acetate on the 503A bulks list^{[2 ]}.

FDA: no identified human exposure data

FDA’s safety-risk page states that FDA has not identified human exposure data for drug products containing Dihexa acetate administered by any route. FDA further states that it lacks important information regarding safety issues raised by Dihexa acetate, including whether it would cause harm if administered to humans^{[4 ]}.

503B and controlled-substance status

For 503B outsourcing facilities, FDA states that a bulk drug substance generally must appear on the 503B bulks list or be used for a drug on FDA’s shortage list at the time of compounding, distribution, and dispensing^{[3 ]}. No FDA-compliant 503B pathway for routine Dihexa compounding was identified.

Dihexa is not listed in federal controlled-substance schedules in 21 CFR Part 1308 as reviewed on May 7, 2026^{[5 ]}. That does not imply FDA approval, lawful compounding, product quality, or clinical safety.

Date of last regulatory verification: May 7, 2026. This section should be rechecked after FDA publishes any PCAC materials or decisions related to Dihexa acetate.

Research summary

Drug-candidate paper with notice of concern: McCoy 2013

The foundational Dihexa drug-candidate paper is McCoy and colleagues’ 2013 JPET article evaluating metabolically stabilized angiotensin IV analogs as procognitive or antidementia agents^{[7 ]}. The authors reported that chemical modifications led to a metabolically stabilized, orally active, blood-brain-barrier-permeant analog and that Dihexa showed activity in scopolamine and aged-rat models^{[7 ]}. However, JPET issued a 2021 notice of concern for this article^{[14 ]}. The paper remains indexed, but the notice means the evidence should be handled cautiously rather than treated as settled.

Mechanism paper retracted: Benoist 2014 → 2025 retraction

The major mechanism paper is more compromised. Benoist and colleagues’ 2014 JPET paper reported that Dihexa and related angiotensin IV-derived peptides acted through HGF/c-Met activation, induced hippocampal spinogenesis and synaptogenesis, and that cognitive effects were blocked by an HGF antagonist^{[8 ]}. JPET issued a notice of concern in 2021 and then published a formal retraction notice in 2025^{[9 –10 ]}. Because of that retraction, the article should not be used as primary support for the HGF/c-Met mechanism.

This does not mean every Dihexa-related hypothesis is disproven. It means the central mechanistic evidence most often cited in promotional summaries is unreliable as a source of factual claims. Independent replication would be needed to reestablish the specific binding, signaling, and mechanism claims from the retracted paper^{[8 –10 ]}.

Independent animal studies

Independent animal studies have continued. Sun and colleagues reported that the AngIV analog Dihexa rescued cognitive impairment and recovered memory in APP/PS1 mice through PI3K/AKT signaling^{[11 ]}. That study provides preclinical Alzheimer model evidence, but mouse APP/PS1 models do not prove human Alzheimer disease efficacy. The outcome measures, dosing, disease biology, and translation to human clinical endpoints remain unresolved.

Wells and colleagues studied an angiotensin IV analog in a 3-nitropropionic-acid-induced Huntington disease-like rat model and reported effects on Huntington disease-like symptoms^{[12 ]}. This is a preclinical toxin-model study, not a clinical trial in people with Huntington disease. It should be cited as animal-model research only.

Other experimental contexts

Other work places HGF-mimetic or HGF/c-Met-related Dihexa analog biology in broader experimental contexts. Uribe and colleagues reported that an HGF mimetic protected lateral line hair cells from aminoglycoside exposure in a zebrafish-relevant model^{[13 ]}. Siller and colleagues used a small-molecule-driven strategy for hepatocyte differentiation from human pluripotent stem cells, with Dihexa included in the small-molecule differentiation literature^{[15 ]}. These studies do not establish Dihexa as a human cognitive therapy.

Reviews have discussed angiotensin IV and angiotensin-(1-7) as experimental cognitive agents and the brain HGF/c-Met system as a possible target in Alzheimer disease^{[16 –17 ]}. Reviews are useful for background, but they predate or do not fully resolve the 2025 retraction problem for Dihexa’s central HGF/c-Met mechanistic paper^{[10 ]}.

Quality-of-evidence assessment

Dihexa has preclinical cognitive and neurobiology research, but no published large randomized human clinical trial was identified as of May 7, 2026. FDA states it has not identified human exposure data for drug products containing Dihexa acetate^{[4 ]}. The most cited 2014 HGF/c-Met mechanism paper has been retracted, and the 2013 drug-candidate paper has a notice of concern^{[8 –10 ,14 ]}. A credible editorial page should therefore classify Dihexa as research-only and avoid claims that it improves memory, treats dementia, repairs the brain, or enhances cognition in humans.

Public discourse

No qualifying public-discourse entries were identified for this page. Search results identified nootropic podcasts, peptide marketing pages, anonymous forum discussion, and secondary summaries, but no accessible named-source medical or scientific podcast transcript with a verifiable quote meeting this site’s citation standard.

The public discourse around Dihexa also includes dosing anecdotes and unsupported “neuroplasticity” claims. Those were excluded because they are not appropriate evidence for an editorial reference page and may encourage unsupervised use of a non-approved compound.

Public discourse reflects the views of the speakers cited and does not represent medical advice or the editorial position of ProPeptideGuide.

Side effects and safety

There is no FDA-approved Dihexa label, so there is no FDA-reviewed adverse-reaction table, contraindication list, drug-interaction profile, pregnancy/lactation language, or postmarketing safety dataset. FDA specifically states that it has not identified human exposure data for Dihexa acetate drug products administered by any route^{[4 ]}.

HGF/MET and cancer-biology context

Theoretical concerns center on the proposed HGF/c-Met biology, while recognizing that the strongest Dihexa-specific mechanism paper has been retracted^{[8 –10 ]}. MET is a proto-oncogene and receptor tyrosine kinase; NCI describes MET as a proto-oncogene and receptor tyrosine kinase gene, and cancer literature identifies HGF/MET activation as an important pathway in multiple malignancies^{[18 –19 ]}. These facts do not prove that Dihexa causes cancer, but they make blanket safety claims inappropriate for any compound proposed to modulate HGF/MET signaling.

Data-integrity concerns

The data-integrity issue is itself a safety consideration. If a central mechanistic paper is retracted and another foundational paper has a notice of concern, then confidence in claims about target engagement, potency, mechanism, and pharmacology is reduced^{[9 –10 ,14 ]}. Lower evidentiary confidence should lead to more conservative public-facing claims.

No human PK/PD or long-term data

No human pharmacokinetic, pharmacodynamic, dose-ranging, reproductive-safety, carcinogenicity, drug-interaction, or long-term exposure dataset was identified for Dihexa as a drug product. Animal-model activity does not establish safe human exposure, especially for repeated use or unsupervised nootropic use.

Product-quality risks

Product-quality risks are substantial. Non-approved Dihexa products may differ in salt form, purity, identity, sterility, endotoxin content, degradation products, storage stability, concentration, and route of administration. These concerns apply especially to injectable products but are not limited to injectables.

Available through

Dihexa is not currently available through FDA-compliant prescription or compounding channels in the United States as of 2026-05-07^{[1 –4 ]}. ProPeptideGuide does not link to or endorse grey-market vendors.