Dihexa

Dihexa (N-hexanoic-Tyr-Ile-(6)-aminohexanoic amide) is a synthetic, metabolically stabilized angiotensin IV (AngIV) analog ². It was designed to survive digestion, reach the bloodstream after oral dosing, and cross the blood-brain barrier, properties the parent peptide lacks ¹. In animal research it binds hepatocyte growth factor (HGF) and strengthens signaling through the c-Met receptor, which promotes formation of dendritic spines and new synapses (synaptogenesis) ¹.

Investigated uses

• Alzheimer's disease and cognitive impairment: multiple animal models, including APP/PS1 mice, show restored learning and memory ⁵.
• Parkinson's disease: motor-dysfunction interest appears in review literature, with only low-confidence support ².
• Huntington's disease: one rat model found no benefit for motor, memory, or weight outcomes ⁶.
• Peripheral nerve repair: rat sciatic nerve studies combine Dihexa with stem cells ⁸.
• Sensory-cell protection: zebrafish work shows protection of lateral-line hair cells from aminoglycoside antibiotics ⁹.
• Regenerative-medicine tool: Dihexa acts as an HGF agonist in stem-cell differentiation protocols for liver-like cells ¹¹.

Where it comes from

Dihexa was developed at Washington State University from Nle1-angiotensin IV, a peptide fragment known for pro-cognitive activity. Medicinal chemistry added a hexanoic acid group and an aminohexanoic amide to improve oral absorption and metabolic stability ³. The HGF/c-Met mechanism was reported in 2014 ⁴. No human clinical trials of Dihexa have been reported, and the broader therapeutic-peptide field in orthopaedics is noted to lack clinical trial data ¹⁰.

Dihexa is not a typical neurotransmitter stimulant. Its core action is trophic: it binds hepatocyte growth factor (HGF) with high affinity and makes the HGF receptor c-Met respond more strongly, even when HGF levels are low ¹. This activates intracellular pro-survival and growth-related signals and leads to new dendritic spines and synapses in hippocampal neurons ¹.

• HGF/c-Met activation: Dihexa binds HGF and promotes c-Met phosphorylation, augmenting HGF-dependent cell responses ⁴.
• Synaptogenesis: In hippocampal neuron studies, Dihexa increased spine and synapse formation at a level comparable to HGF itself, and these effects disappeared when HGF or c-Met was blocked ⁴.
• PI3K/AKT downstream signaling: In APP/PS1 mice, Dihexa activated the PI3K/AKT pathway; a PI3K inhibitor reversed its anti-inflammatory and anti-apoptotic effects ⁵.
• Target dependence: Blocking HGF with an antagonist also blocked the memory benefit of orally delivered Dihexa in the Morris water maze ⁴.
• Brain access: The N-terminal and C-terminal modifications make Dihexa lipophilic, stable, and able to cross the blood-brain barrier in rodents ³.

A contested identity question remains: the angiotensin IV AT4 site has historically been proposed to be insulin-regulated aminopeptidase (IRAP), while the pro-cognitive activity appears to overlap the HGF/c-Met system ¹.

All efficacy data for Dihexa are preclinical, so effects below describe animal and cell models rather than human outcomes ¹⁰.

Cognition and memory

• In scopolamine-impaired rats, oral Dihexa reversed Morris water maze deficits and restored hippocampal synaptogenesis ³.
• In aged rats, oral Dihexa improved water maze performance and was associated with synaptogenesis ³.
• In APP/PS1 Alzheimer's-model mice, oral Dihexa restored spatial learning and memory, increased neuronal counts and the synaptic marker synaptophysin, and reduced inflammatory signaling ⁵.
• A systematic review found AngIV analogs, including Dihexa, improved cognition in eight of nine cognitive-deficit studies, with the largest benefits when given near learning or retention testing ⁷.

Neuroprotection and tissue repair

• Combined with mesenchymal stem cells in a rat sciatic nerve transection-repair model, Dihexa at 2-4 mg/kg improved motor function and reduced foot flexion contractures ⁸.
• In zebrafish, 1 µM Dihexa protected lateral-line hair cells from neomycin and gentamicin toxicity ⁹.
• As an HGF agonist, Dihexa has been used in vitro to help drive human pluripotent stem cells toward hepatocyte-like cells ¹¹.

Negative result

• In a 3-nitropropionic acid Huntington's-like rat model, Dihexa did not protect against weight loss, motor dysfunction, or memory deficits over five weeks ⁶.

Dihexa has no published human dosing trials. The schedules below are drawn from animal efficacy studies and community-level research practice; none is an established human therapeutic protocol.

• Published animal anchors: Rat sciatic nerve-repair studies used 2-4 mg/kg delivered by local hydrogel, intravenous, or intraperitoneal routes together with stem-cell therapy ⁸. A rat vascular composite allotransplantation model used 2 mg/kg locally and intravenously ¹³.
• Oral cognition models: Scopolamine-deficit, aged-rat, and APP/PS1 mouse studies used oral dosing, with APP/PS1 work testing multiple doses ³.
• Zebrafish ototoxicity model: Bath exposure at 1 µM produced optimal hair-cell protection ⁹.
• Community cognitive cycle: Community protocols commonly describe 10-40 mg/day orally for 4-8 weeks, followed by 2-4 weeks off (community protocol). Subcutaneous use is reported at similar daily totals, but no published human injectable data exist (community protocol).
• Allometric estimate only: Rat doses of 2-4 mg/kg convert to a human-equivalent range of roughly 0.32-0.65 mg/kg, about 20-45 mg for a 70 kg adult, using standard allometric scaling. This is an extrapolation, not a validated human dose.

Animal work also suggests timing matters: cognitive benefits were most reliable when AngIV analogs were given close to learning acquisition or retention testing, usually by direct intracerebroventricular delivery rather than chronic oral use ⁷. Community protocols tend to favor morning administration and oral dosing with a fat-containing meal (community protocol).

Dihexa is a highly lipophilic compound, because its N- and C-terminal modifications reduce how readily it dissolves in water ². Community protocols therefore avoid plain bacteriostatic water, which produces clumping and incomplete dissolution, and instead use high-purity pharmaceutical-grade DMSO as the primary solvent (community protocol). DMSO can also be diluted with sterile water for subcutaneous preparations (community protocol).

Handling notes from community protocols:

• Add diluent slowly down the vial wall and swirl gently; do not shake (community protocol).
• Pass preparations through a 0.22 µm filter when sterile filtration is required (community protocol).
• Keep dry powder frozen at about -20°C for long-term storage, or refrigerated at 2-8°C for short-term use (community protocol).
• Store reconstituted solutions refrigerated and use within roughly 14-30 days; freeze aliquots only if needed and limit freeze-thaw cycles (community protocol).

The interactive calculator below can work out diluent volume and concentration from the vial size and desired research dose.

No human interaction studies exist for Dihexa, so the interactions below come from mechanistic work, animal experiments, and community practice.

• Anticholinergics: Dihexa reversed scopolamine-induced memory deficits in rats ³. In theory, anticholinergic drugs oppose Dihexa's cognitive effect, while Dihexa may partially offset anticholinergic cognitive burden.
• Aminoglycoside antibiotics: Dihexa protected zebrafish lateral-line hair cells from neomycin and gentamicin toxicity at 1 µM without reducing drug uptake ⁹. This is a potential protective interaction rather than an antagonism.
• PI3K, TOR, and MEK inhibitors: Wortmannin reversed Dihexa's anti-inflammatory and anti-apoptotic effects in APP/PS1 mice, and related inhibitors attenuated its otoprotection in zebrafish ⁵. These drug classes may blunt Dihexa's expected benefit.
• HGF/c-Met antagonists: HGF antagonists block Dihexa's pro-cognitive and cytoprotective activity ⁴. c-Met kinase inhibitors would be expected to oppose it as well.
• Cholinesterase inhibitors and memantine: No interaction data exist, though community add-on use is reported with monitoring for sleep and agitation (community protocol).

Supplement and peptide combinations

• Forskolin and vitamin C: In vitro, the vitamin C plus Dihexa plus forskolin (VDF) cocktail replaced growth factors to drive liver-lineage differentiation of human pluripotent stem cells ¹¹.
• Mesenchymal stem cells and G-CSF: Supported in a rat nerve-repair model when combined with Dihexa ⁸.
• Semax and Selank: Overlapping neuroplasticity pharmacology with no direct interaction data (community protocol).
• BPC-157 and TB-500: Theoretical additive tissue-repair signaling, with caution raised for anyone with malignancy concerns because of pro-growth pathway overlap (mechanistic).

The research does not document tolerance or tachyphylaxis for Dihexa. Instead, cycling in community protocols is driven by the unknown long-term safety of continuously activating c-Met, a receptor involved in cell growth and tissue remodeling ¹.

• Common cycle: 4-8 weeks on followed by 2-4 weeks off, at 10-40 mg/day oral or subcutaneous (community protocol).
• Alternative pattern: 5 days on, 2 days off for ongoing use without a full washout (community protocol).
• Learning-paired pattern: Some community protocols pair 2-4 week blocks with structured learning or training blocks (community protocol).

Two observations from the animal literature shape these patterns. First, AngIV analogs produced the most reliable cognitive benefit when administered near learning acquisition or retention testing ⁷, so cycling around structured learning periods mirrors the condition in which benefit was shown. Second, chronic c-Met activation drives mitogenesis and morphogenesis across cell types ¹, which is the primary reason community protocols schedule off-periods even though no human safety data exist (community protocol).

Signs community protocols use to trigger a break include plateaued memory benefit after roughly 3-6 weeks, sleep disruption, agitation, and any blood pressure drift (community protocol). No validated human bloodwork or biomarker exists for Dihexa effectiveness.

Dihexa has no human stacking trials, but its mechanism suggests distinct combination roles, and some animal combinations have been tested.

• Stem cells and G-CSF: In rat sciatic nerve injury, mesenchymal stem cells plus Dihexa improved motor recovery at 8-16 weeks ⁸. G-CSF combinations were similarly effective in the same model ⁸.
• GH secretagogues: Peptides such as ipamorelin, CJC-1295, sermorelin, and tesamorelin act through IGF-1 and satellite-cell repair pathways distinct from HGF/c-Met, so no shared rate-limiting node has been identified (mechanistic).
• BPC-157 and TB-500: These share pro-angiogenic and tissue-repair outputs, and Dihexa adds HGF-driven cell growth signaling. Additive repair signaling is plausible, but the combination is generally avoided in anyone with malignancy concerns (mechanistic).
• Semax and Selank: Practitioner communities describe stacking for overlapping neuroplasticity effects, although direct combination studies are absent (community protocol).
• Pairs to avoid: HGF antagonists or c-Met kinase inhibitors would directly oppose Dihexa's mechanism ⁴, and mTOR, PI3K, or MEK inhibitor therapy would be expected to blunt its downstream effects ⁵.

Because chronic HGF/c-Met activation is the main theoretical safety concern, combinations that add further growth signaling should be evaluated with that risk in mind ¹.

Dihexa has no regulatory approval in the United States or any other jurisdiction, and no human clinical trial program has been registered ¹⁰. It is sold as a research chemical with 'not for human consumption' labeling.

• United States: Not FDA-approved. It is not a dietary supplement under DSHEA, has no New Dietary Ingredient notification, and appears on neither the 503A nor 503B bulks lists, so lawful bulk compounding for human use is unavailable (regulatory analysis). It is not scheduled under the Controlled Substances Act.
• International: No EMA, MHRA, or TGA authorization exists. United Kingdom supply for human consumption could theoretically face challenge under the Psychoactive Substances Act 2016 given pro-cognitive activity, though research-chemistry sales continue under non-human-use frameworks (regulatory analysis).
• Sports: Dihexa is not named on the WADA Prohibited List, but its non-approved status places it under WADA category S0, which prohibits non-approved substances at all times in and out of competition. A Therapeutic Use Exemption is generally unavailable for S0 substances (practitioner consensus).
• Clinical development: Developed academically at Washington State University as a first-in-class orally active, blood-brain-barrier-penetrant angiotensin IV analog, but no commercial sponsor has carried it into human testing ².

No human safety data exist for Dihexa. Animal studies at the tested doses generally report no compound-specific adverse events ⁶.

Reported and theoretical side effects

• Community-reported, usually mild: insomnia with late-day dosing, headache in the first days, mild irritability, gastrointestinal upset after oral dosing, and injection-site reactions with subcutaneous use (community protocol).
• Overstimulation at higher doses: community reports describe agitation, anxiety, sleep fragmentation, and elevated resting blood pressure, typically after multi-week cycles without breaks; these reverse with dose reduction or washout (community protocol).
• Theoretical oncogenic risk: Dihexa activates c-Met, a pathway that drives cell proliferation, movement, and morphogenesis ¹. No carcinogenicity studies exist, but chronic activation is mechanistically concerning.
• Theoretical hyperexcitability: marked hippocampal synapse formation could lower seizure threshold, though no seizures are reported in animal work ⁴.
• Structural specificity: a single amino-group change at the N-terminus sharply attenuated protection, so impure or altered product carries uncertain off-target risk ⁹.

Contraindications drawn from mechanism

• Active malignancy or a history of c-Met-driven cancers, because Dihexa directly activates the receptor ¹.
• Pregnancy, attempted conception, and breastfeeding, due to absent reproductive safety data and the deep involvement of HGF/c-Met in embryonic development ¹.
• Epilepsy, uncontrolled hypertension, active mania or psychosis, and concurrent c-Met or PI3K/MEK/mTOR inhibitor therapy are listed as relative contraindications in the research literature (mechanistic).
• Huntington's disease: one rat model found no benefit, and there is no supportive efficacy signal ⁶.

Unknowns

Human toxicity, chronic c-Met agonism beyond six months, drug interactions, route-dependent safety for subcutaneous injection, and sleep or mood effects in healthy users remain untested ¹⁰.