Dihexa

Dihexa is a small-molecule analog of angiotensin IV developed as an orally active compound that crosses the blood-brain barrier The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases+1. Research indicates it acts primarily by activating the hepatocyte growth factor (HGF) receptor c-Met, a pathway involved in nerve cell survival, synapse formation, and brain repair RETRACTED: The Procognitive and Synaptogenic Effects of Angiotensin IV–Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met System+1. Preclinical studies have investigated Dihexa for cognitive impairment, hearing protection, and nerve regeneration, though no human trials have been conducted AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway+2. Its utility is most established as a tool compound in stem cell differentiation protocols, where it substitutes for recombinant HGF at nanomolar concentrations Comparative analysis of small molecule and growth factor-derived human induced pluripotent stem cell-derived hepatocyte-like cells+1.

Dihexa appears to enhance HGF/c-Met signaling, which in turn promotes synaptic growth (synaptogenesis) and neuronal survival The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases+1. In the brain, HGF and its receptor c-Met support neuron development, guide axon growth, and reduce inflammation HGF and MET: From Brain Development to Neurological Disorders+1. When Dihexa activates c-Met, it triggers downstream pathways including PI3K/AKT, a key regulator of cell survival and protein synthesis AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. In Alzheimer's disease mouse models, Dihexa increased synapse markers and improved spatial memory, effects that were blocked by PI3K inhibition AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. This places HGF/c-Met activation at the center of Dihexa's proposed mechanism.

While direct high-affinity binding of Dihexa to HGF has not been reported in the available literature, other preclinical data and its consistent use as a c-Met agonist in liver and neuronal cell cultures confirm functional activity via this pathway Comparative analysis of small molecule and growth factor-derived human induced pluripotent stem cell-derived hepatocyte-like cells+1.

Preclinical research has documented several effects of Dihexa, although evidence varies by model.

In APP/PS1 mice (an Alzheimer's disease model), Dihexa improved spatial learning and memory, increased neuronal markers, reduced inflammatory glial activation, and lowered pro-inflammatory cytokines like IL-1β and TNF-α while raising anti-inflammatory IL-10 AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway. These cognitive benefits were accompanied by activation of the PI3K/AKT signaling pathway AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.

The effect of Dihexa on sensory hair cells has not been examined in the available literature. In a rat sciatic nerve injury model, Dihexa combined with stem cells improved motor recovery and reduced contractures, but its individual contribution was not isolated Stem cell, Granulocyte-Colony Stimulating Factor and/or Dihexa to promote limb function recovery in a rat sciatic nerve damage-repair model: Experimental animal studies.

Notably, Dihexa failed to prevent motor or cognitive deficits in a rat model of Huntington's disease, indicating that its effects are not universal across neurodegenerative conditions Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Outside animal models, Dihexa is widely used in stem cell and organoid research at 100 nM to promote liver cell maturation, confirming its c-Met agonist activity in human cells Comparative analysis of small molecule and growth factor-derived human induced pluripotent stem cell-derived hepatocyte-like cells+1.

Research protocols for Dihexa vary by route and goal. The most published route is oral, as Dihexa was designed to be orally active and brain-penetrant The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases+1. Injectable use is based on community practice rather than published PK data (community protocol).

Typical oral research protocols start with lower doses of 5–20 mg once daily for 2–4 weeks to assess tolerability, often with morning dosing to avoid sleep disruption (community protocol). If well-tolerated, the dose is frequently increased to 20–45 mg daily for 4–8 weeks, targeting neurotrophic effects. Cycling patterns such as 5 days on/2 days off or 8 weeks on/2–4 weeks off are reported, although continuous daily use also appears in some protocols (community protocol).

Injectable protocols are less standardized and generally range from 0.05–0.5 mg/kg subcutaneously once daily (practitioner consensus). Because of limited solubility in water, DMSO is often used for stock solutions in laboratory settings, but this approach is not intended for human administration.

No human clinical trials define an optimal dose or duration; all protocols derive from animal studies and community experience AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway+1.

Dihexa is a stable small molecule and is often handled as a DMSO stock for laboratory use Comparative analysis of small molecule and growth factor-derived human induced pluripotent stem cell-derived hepatocyte-like cells+1. For research, it should first be dissolved in a sterile solvent like DMSO to create a concentrated stock, then diluted into media or aqueous solution immediately before use (practitioner consensus).

If an aqueous solution is required, bacteriostatic water may be used, though solubility may be lower. The lyophilized powder is best stored at −20 °C for long-term stability; reconstituted DMSO stocks can be kept at −20 °C for months if divided into single-use aliquots to avoid freeze–thaw cycles (community protocol). Aqueous solutions are less stable, should be refrigerated, and used within 14–30 days (community protocol). An interactive reconstitution calculator is available below to determine precise volumes.

No formal drug interaction studies exist for Dihexa. Because it engages the HGF/c-Met and PI3K/AKT pathways, theoretical concerns exist with agents that affect growth signaling or liver metabolism ​Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology+2.

Combining Dihexa with sedatives or alcohol may mask its cognitive effects, while stimulants could lead to overstimulation (community protocol). Caution is advised with anticancer drugs, as c-Met activation can theoretically promote tumor growth Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies+1. Dihexa is used in hepatic cell models, so metabolism by liver enzymes is plausible but unstudied; individuals on multiple hepatically cleared medications should monitor liver function ​Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology+1. Additionally, as an angiotensin IV analog, Dihexa may theoretically influence blood pressure or vascular function via the renin-angiotensin system, though no studies are available.

With supplements, overlap with other nootropics or cognitive enhancers may cause unpredictable effects. Separating introductions by 1–2 weeks is a common research practice (community protocol).

In research communities, Dihexa is often combined with other peptides or compounds to target different aspects of cognitive and neural repair. Common stacks include:

• BPC-157: For additive nerve and tissue repair; Dihexa provides HGF-driven synaptic support while BPC-157 supports angiogenesis and healing (community protocol).
• GH secretagogues like ipamorelin or CJC-1295: Theoretically complement HGF/c-Met signaling with GH/IGF-1 pathways, which also influence neuroplasticity Chemical approaches targeting the hurdles of hepatocyte transplantation: mechanisms, applications, and advances+1. Combine cautiously due to overlapping growth factor activity.
• Semax/Selank: Both are neuroprotective peptides; some practitioners stack them for broader cognitive benefit, but effects may be additive or unpredictable (community protocol).
• GHK-Cu: Used for systemic repair; its copper-dependent actions are distinct from HGF signaling, so conflict is unlikely (practitioner consensus).

No peer-reviewed human combination trials exist. When stacking, it is typical to introduce one compound at a time to assess individual response (community protocol).

Dihexa is not FDA-approved for any indication in the United States, nor is it approved by the European Medicines Agency or Australian TGA The Occurrence of Illicit Smart Drugs or Nootropics in Europe and Australia and Their Associated Dangers: Results from a Market Surveillance Study by 12 Official Medicines Control Laboratories. International market surveillance identifies it as a "research chemical" often sold in unregulated nootropic products The Occurrence of Illicit Smart Drugs or Nootropics in Europe and Australia and Their Associated Dangers: Results from a Market Surveillance Study by 12 Official Medicines Control Laboratories. It is not scheduled by the DEA according to available data, but it remains an investigational compound with no established human medical use The Occurrence of Illicit Smart Drugs or Nootropics in Europe and Australia and Their Associated Dangers: Results from a Market Surveillance Study by 12 Official Medicines Control Laboratories.

Athletes should note that Dihexa has not been explicitly listed by WADA, but its presence as an ingredient in contaminated supplements introduces doping test risk The Occurrence of Illicit Smart Drugs or Nootropics in Europe and Australia and Their Associated Dangers: Results from a Market Surveillance Study by 12 Official Medicines Control Laboratories. The compound's development was oriented toward research and stem cell protocols rather than clinical therapeutics Comparative analysis of small molecule and growth factor-derived human induced pluripotent stem cell-derived hepatocyte-like cells+1.

Human safety data for Dihexa are not available. Preclinical findings and mechanistic considerations point to several areas of concern.

Common side effects reported in community research settings include headache, vivid dreams, insomnia, and mild irritability, especially at higher doses (community protocol). These are likely related to its neuroactive properties.

The most significant theoretical risk is tumor promotion, because chronic HGF/c-Met activation can enhance cell proliferation, survival, and angiogenesis Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies+1. Dihexa should be strictly avoided in anyone with active cancer or a history of malignancy. It is also contraindicated in pregnancy, lactation, and pediatric populations due to the role of HGF in development Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies.

Liver function should be monitored, as Dihexa is used in liver maturation protocols and its metabolism is undefined ​Temporal proteomic profiling of iPSC-derived human liver organoids reveals optimal maturation for drug metabolism and toxicology+1. Psychosis, bipolar disorder, and seizure disorders are relative contraindications due to potential neuroexcitation (community protocol).

No long-term human safety data exist; the duration of use in research settings should be limited, with interval monitoring of liver enzymes, glucose, and neurological status (practitioner consensus).