Dihexa

Dihexa (systematic name N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide; also designated PNB-0408) is a synthetic, metabolically stabilized small peptide derived from angiotensin IV (AngIV), the hexapeptide fragment of angiotensin II. Its Tyr-Ile dipeptide core is flanked by an N-terminal hexanoyl cap and a C-terminal 6-aminohexanoic amide, modifications that resist proteolytic degradation and confer meaningful oral bioavailability — unusual properties for a peptide-based compound.

The proposed mechanism targets the hepatocyte growth factor (HGF) / c-Met receptor tyrosine kinase signaling axis. Research from Washington State University (Harding laboratory) claimed that dihexa binds HGF with picomolar affinity, facilitates HGF dimerization, and acts as a positive allosteric potentiator at the c-Met receptor, amplifying downstream signals including PI3K/AKT. An independent 2021 study in APP/PS1 transgenic mice confirmed PI3K/AKT pathway involvement and documented reduced hippocampal neuroinflammatory markers. Dendritic spine formation and new glutamatergic synapse assembly (synaptogenesis) are proposed as the cellular correlates of observed cognitive effects.

A critical caveat: the 2014 paper that formally quantified HGF-binding affinity (Kd = 65 pM) and attributed synaptogenesis to c-Met activation was retracted in April 2025 after a Washington State University investigation found that key figures contained falsified and fabricated data, attributed to co-authors Kawas and Harding. The companion 2013 paper carries a Notice of Concern for related misconduct. These actions materially undermine the published mechanistic model.

Pharmacokinetically, dihexa shows an estimated plasma half-life of approximately 335 minutes in microsomal assays and a circulating half-life of roughly 12.7 days in rats, with documented blood-brain barrier penetration and predicted oral jejunal permeability.

No human clinical trials of dihexa itself have been registered or completed as of mid-2026. All direct evidence comes from rodent behavioral studies and in vitro models, portions of which carry serious data integrity concerns.

McCoy et al. (J Pharmacol Exp Ther, 2013; PMID 23055539; Notice of Concern issued 2021) demonstrated that oral dihexa at 1.25-2.0 mg/kg reversed scopolamine-induced amnesia and restored spatial learning in aged rats using the Morris water maze; treated groups became statistically indistinguishable from unimpaired controls by day five of testing. The same study reported a circulating half-life of approximately 12.7 days and negligible Phase I microsomal metabolism, supporting oral bioavailability. This paper is subject to a Notice of Concern tied to the broader Washington State University research misconduct investigation.

Sun et al. (Brain Sciences, 2021; PMID 34827486), an independent Chinese research group with no connection to the misconduct proceedings, administered dihexa intragastrically at 1.44 mg/kg and 2.88 mg/kg for three months in APP/PS1 transgenic mice modeling amyloid-driven pathology. Dihexa-treated mice showed improved Morris water maze performance, reduced cortical neuronal loss on Nissl staining, decreased astrocyte activation (GFAP), reduced microglial activation (Iba-1), lower pro-inflammatory cytokines (TNF-alpha, IL-1beta), and elevated anti-inflammatory IL-10. Effects were reversed by the PI3K inhibitor wortmannin.

The closest human evidence comes from fosgonimeton (ATH-1017), a related HGF/MET modulator developed from the same Washington State University program. A randomized Phase 1 trial (NCT03298672; n = 88, healthy volunteers and Alzheimer patients, subcutaneous doses 2-90 mg) found the agent safe with dose-proportional pharmacokinetics and pharmacodynamic EEG signals. However, the Phase 2/3 LIFT-AD trial (NCT04886063; n = 315, 26 weeks, 40 mg SC daily) failed all primary and key secondary cognitive endpoints in mild-to-moderate Alzheimer disease (GST primary p = .70; ADAS-Cog11 p = .35). All fosgonimeton clinical programs were discontinued in September 2024.

Typical dosage: Research protocols vary (research).

No human dose for dihexa has been established in any clinical trial, regulatory submission, or approved prescribing label. The following reflects preclinical animal data and community anecdotal reports only.

In rodent studies, effective doses ranged from 0.1-1.0 nmol intracerebroventricularly, 0.05-0.50 mg/kg intraperitoneally, and 1.25-2.0 mg/kg orally. These doses reversed pharmacologically induced amnesia and age-associated cognitive decline. The independent Sun 2021 study used intragastric doses of 1.44 mg/kg and 2.88 mg/kg over three months.

Applying standard FDA allometric scaling, a rat oral effective dose of approximately 2 mg/kg translates to roughly 0.32 mg/kg in a 70-kg adult, or approximately 22 mg. This extrapolation is entirely speculative in the absence of any validated human pharmacokinetic data.

Anecdotal reports in online peptide research communities describe: • Oral dosing: 10-40 mg once daily • Subcutaneous dosing: 2-10 mg once daily • Cycle length: 4-6 weeks on, followed by 2-4 weeks off

The cycling rationale is the compound's long estimated half-life (~12-13 days in rat plasma), which would produce accumulation with continuous daily dosing. These community protocols are unvalidated and represent extrapolation from animal data of contested reliability.

For context, the related compound fosgonimeton was dosed at 40 mg subcutaneously once daily in its Phase 2/3 human trial, but fosgonimeton is a distinct prodrug formulation and its dosing does not directly apply to dihexa.

This information is provided for educational and scientific reference purposes only and does not constitute medical advice. Dihexa has not been approved by any regulatory authority, and its safety and efficacy in humans have not been established.

No compound-specific stability data has been identified for this peptide. The general lyophilized-peptide handling framework applies — see Storage & handling for temperature, reconstitution diluent, and beyond-use dating principles.

No controlled preclinical or clinical studies have examined dihexa in combination with any other compound. All reported combination use is anecdotal and unverified.

Community-reported stacks most frequently pair dihexa with Semax (an ACTH4-10 heptapeptide analog with reported BDNF-upregulating activity developed in Russia) and Selank (a tuftsin-based hexapeptide analog with reported anxiolytic and GABAergic modulating properties, also of Russian origin). The stated rationale is mechanistic complementarity and temporal layering: Semax and Selank are short-acting compounds with rapid subjective onset, whereas dihexa's proposed synaptogenic effects are hypothesized to accumulate over days to weeks. This combination is entirely anecdotal and has no controlled safety or efficacy data.

Some community users add racetam-class compounds (e.g., aniracetam, oxiracetam) or NAD+ precursors on the basis of non-overlapping hypothesized mechanisms. No interaction data exist.

Given uncharacterized safety concerns for dihexa alone, the risks of any combination are unknown and likely additive in complexity. All combination strategies described here reflect anecdotal community use only.

Dihexa is not currently FDA-approved for any indication. Effective April 22, 2026, the FDA removed Dihexa from Category 2 of its Section 503A bulk drug substances list after the original nominators withdrew their nominations. This removal lifts the prior “significant safety risk” designation but does not place Dihexa on the 503A Bulks List. Compounding pharmacies may prepare it with a valid physician prescription and pharmaceutical-grade API from an FDA-registered manufacturer. The FDA’s Pharmacy Compounding Advisory Committee (PCAC) is scheduled to review this substance at its July 23–24, 2026 public meeting. Removed from FDA Category 2 effective April 22, 2026. NOT selected for July 23-24, 2026 PCAC meeting. Deferred to second PCAC meeting before February 2027. NOT currently on 503A Bulks List — requires physician Rx. Source: FDA Advisory Committee Calendar / Lengea Law, May 2026.

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Reported side effects: Research compound. Long-term effects unknown

The human safety profile of dihexa is entirely unknown. No clinical pharmacology, toxicology, or Phase 1 safety study has been conducted in humans. Adverse effect information consists entirely of rodent extrapolations and unverified anecdotal reports.

The most significant theoretical concern is the compound's proposed mechanism. The HGF/c-Met pathway is a validated oncogene overexpressed in lung, breast, hepatocellular, gastric, and renal cancers; aberrant c-Met signaling drives tumor proliferation, invasion, angiogenesis, and metastasis. Multiple approved oncology drugs (capmatinib, tepotinib, crizotinib) act as c-Met inhibitors. Dihexa is proposed to act as the pharmacological opposite — a c-Met potentiating agonist. No carcinogenicity study of any duration has been conducted in any species, so this risk is theoretical but structurally plausible and entirely uncharacterized.

The estimated plasma half-life of approximately 12.7 days in rats implies substantial accumulation with repeated daily dosing and a prolonged clearance period of many weeks after discontinuation.

Crucially, the foundational dihexa mechanistic literature — Benoist 2014 retracted for data fabrication; McCoy 2013 under Notice of Concern — means both efficacy claims and the mechanistic risk model rest on compromised science.

Rodent behavioral studies were not designed to detect adverse events; no systematic toxicology data have been published for dihexa in any species.

Anecdotal user reports from online communities mention headache, anxiety, sleep disruption, and gastrointestinal discomfort, but none of these reports can be attributed causally.

For reference, the structurally related compound fosgonimeton was generally well-tolerated in human trials at subcutaneous doses up to 90 mg, with injection site reactions as the primary adverse event and transient eosinophilia noted. All fosgonimeton clinical development was discontinued in September 2024 following failure of the LIFT-AD trial.