Dihexa
N-Hexanoyl-Tyrosine-Isoleucine / PNB-0408
Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide) is a synthetic oligopeptide developed at Washington State University as an angiotensin IV analog that acts as a potent hepatocyte growth factor (HGF) receptor (c-Met) agonist. It is approximately 10 million times more potent than BDNF at promoting synaptogenesis in vitro, making it one of the most powerful cognitive-enhancing compounds ever identified in preclinical research. Dihexa was designed to be orally bioavailable and blood-brain barrier permeable, distinguishing it from earlier angiotensin IV analogs that required direct CNS administration.
Mechanism of Action
Angiotensin IV analog that activates hepatocyte growth factor (HGF) signaling via the c-Met receptor. Promotes synaptogenesis, dendritic spine formation, and neuronal connectivity. Approximately 10 million times more potent than BDNF at promoting synaptic connections.
Research Protocols
For research purposes only. Not medical advice.
Research protocols are primarily animal-based. Oral dosing studied in rats at 0.5-2mg/kg. Human protocols not established but anecdotal reports use 10-40mg orally or 5-20mg sublingually.
Research Notes
Clinical Research Status
Dihexa remains exclusively in preclinical research with no human clinical trials initiated or registered. All published data originates from the laboratory of Joseph Harding and colleagues at Washington State University, with key papers published between 2013 and 2015. A patent was filed (US Patent 8,598,118) for the treatment of cognitive deficits including Alzheimer's disease, but no pharmaceutical company has publicly advanced it toward clinical development. The extreme potency and novel mechanism make it both scientifically significant and under-characterized for human safety.
Key Published Findings
The foundational 2013 paper in the Journal of Pharmacology and Experimental Therapeutics demonstrated Dihexa augments HGF/c-Met signaling to promote synaptogenesis at picomolar concentrations (10^-13 M). Animal studies showed restoration of cognitive function in scopolamine-impaired and aged rats using Morris water maze and novel object recognition paradigms. Dihexa was shown to cross the blood-brain barrier when administered orally, intraperitoneally, or intranasally in rodent models. The mechanism involves stabilization of HGF and facilitation of c-Met dimerization, amplifying an endogenous neurotrophic signaling system rather than introducing an exogenous one.
Safety Profile
No formal toxicology or safety studies have been published for Dihexa in any species at therapeutic doses. The primary theoretical safety concern centers on c-Met being a well-established proto-oncogene; aberrant HGF/c-Met signaling drives tumor growth, invasion, and metastasis in multiple cancer types. Short-term animal studies (weeks) showed no obvious adverse effects, but long-term carcinogenicity data does not exist. The compound's extreme potency means even small dosing errors could produce dramatically supratherapeutic exposure, and the consequences of chronic c-Met activation on cancer risk remain completely unknown.
Drug Interactions & Contraindications
Dihexa should be considered absolutely contraindicated in anyone with a personal history of cancer, active malignancy, or strong family history of c-Met-driven cancers (gastric, hepatocellular, renal cell, non-small cell lung cancer). Concurrent use with other growth factor-promoting compounds (GH secretagogues, IGF-1, TB-500) may compound theoretical oncogenic risk. No formal drug interaction studies exist, though c-Met pathway crosstalk with EGFR and other receptor tyrosine kinases suggests complex potential interactions with targeted cancer therapies. Patients taking angiotensin receptor blockers (ARBs) should note that Dihexa acts on the AT4 receptor system which is distinct from AT1/AT2.
Comparison to Related Compounds
Dihexa is approximately 7 orders of magnitude (10 million-fold) more potent than BDNF at promoting new synaptic connections, though through an entirely different receptor system (c-Met vs. TrkB). Compared to other nootropic peptides (Semax, Selank), Dihexa operates through a unique growth factor mechanism rather than neurotransmitter modulation, potentially producing structural rather than merely functional cognitive enhancement. Unlike racetams or modafinil which modulate existing synaptic activity, Dihexa promotes the physical formation of new synapses (synaptogenesis). Its oral bioavailability and BBB permeability distinguish it from most peptide nootropics which require nasal or injectable administration.
Community Observations
Users typically dose Dihexa at 10-30 mg sublingually or orally, though the evidence base for these doses is extrapolated from rodent studies without formal human pharmacokinetic data. Reports describe profound improvements in memory formation, spatial reasoning, and learning speed, often noticed within days of initiation. The community remains sharply divided on risk tolerance given the c-Met oncogene concerns, with many experienced peptide users choosing to avoid Dihexa despite its remarkable nootropic potential. Those who use it typically limit courses to 2-4 weeks followed by extended breaks, reasoning that brief synaptogenesis promotion may yield lasting structural benefits while minimizing chronic c-Met activation.
Half-Life
~Unknown
Reconstitution
DMSO or PEG-400 for sublingual; oral capsule
Storage
Lyophilized
Store at -20C. Protect from light.
Reconstituted
Store at -20C in solution.
US Legal Status
Also Known As
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