Dihexa
Synaptogenic Peptide · Cognitive Enhancement
Dihexa is a synthetic oligopeptide derived from angiotensin IV that potently enhances cognitive function by promoting synaptogenesis. It is 10 million times more potent than BDNF at promoting synapse formation through HGF/c-Met receptor activation.
Overview
Dihexa is a synthetic oligopeptide derived from angiotensin IV that potently enhances cognitive function by promoting synaptogenesis. It is 10 million times more potent than BDNF at promoting synapse formation through HGF/c-Met receptor activation.
Binds to hepatocyte growth factor (HGF) with high affinity (Kd = 65 pM) and potentiates its activity at c-Met receptor, activating PI3K/AKT pathways and promoting new synaptic connections with extraordinary potency.
Research indications
What the compound has been studied for, grouped by body system. Effect size is the reported magnitude where it was measured — not a recommendation.
Improvements in spatial, working, and consolidation demonstrated across animal models.
Enhanced acquisition through increased synaptic plasticity.
Restoration in impairment models including scopolamine-induced amnesia.
Reduced amyloid burden in Alzheimer's models.
Decreased neuroinflammation and glial activation.
Protection of synapses in neurodegeneration models.
3-fold increase in dendritic spine formation demonstrated.
Increases brain-derived neurotrophic factor expression.
Promotes new blood vessel formation in brain.
A large effect in a weak study and a small effect in a strong one are different things. Effect size is never evidence of use in people.
- Class
- Modified oligopeptide
- Molecular weight
- 504.7 Da
- Half-life
- ~240 h
- Typical dose
- 8-10mg oral or 2-5mg injectable (0.5mg/kg based on research)
- Frequency
- Once daily in the morning
- Cycle length
- 4-8 weeks on
- Storage
- Oral: room temperature (2 year shelf life); Injectable lyophilized: 2-8°C; Reconstituted: 2-8°C, use within 30 days
Molecular data
- Type
- Modified oligopeptide
- Molecular weight
- 504.7 Da
- Half-life
- 14400 min
Dosing reference
Doses reported in the literature and by suppliers. These are a record of what has been used in research — reference, never instruction.
| Context | Route | Amount | Frequency |
|---|---|---|---|
| Standard cognitive enhancement | Oral | 8-10mg | 1x daily (morning) |
| Low-dose maintenance | Oral | 5mg | 1x daily |
| Intensive learning protocol | Oral | 10-15mg | 1x daily |
| Research protocol | SubQ/IP | 0.5mg/kg daily | Daily or 3x weekly |
| Standard injectable | SubQ | 2-5mg total | 1x daily |
| Topical application | Inner forearms, shoulders (rotate sites) | 10-20mg cream | 1x daily |
Interactions
Enhanced cognitive benefits; monitor for overstimulation.
Synergistic effects; watch for neural overstimulation.
Different mechanisms; no negative interactions known.
Both affect neuroplasticity strongly; avoid concurrent use.
Some stack for cognition; limited safety data.
Complementary mechanisms for cellular health.
Both potently neuroactive; may cause overstimulation.
Different targets; no known interactions.
Quality checklist
- ✓Pharmaceutical-grade from licensed compounding pharmacy
- ✓Certificate of analysis showing >98% purity
- ✓Proper storage conditions maintained
- ✓Uniform capsules with clear lot numbers and expiration dates
- !Research chemical sources may lack pharmaceutical standards
- !Products lacking third-party testing documentation
- ×No analytical testing or purity reports
- ×Unverified sources
- ×Suspicious or extremely cheap pricing
- ×Discolored or damaged capsules
What to expect
Safety
- Headaches (most frequent side effect)
- Anxiety or overstimulation
- Sleep disruption when dosed late in day
- Mental clarity increase
- Severe or persistent headaches
- Increasing anxiety or panic attacks
- Significant mood changes or depression
- Sleep disturbance beyond 3 days
- Concerning neurological symptoms
- Signs of overstimulation or mania
- Injection site reactions (if injectable)
- Not FDA approved - research compound only
- Theoretical cancer risk via c-Met activation
- Cancer history (avoid due to c-Met pathway)
- Pregnancy or breastfeeding
- No long-term human safety data
FAQ
How much more potent is Dihexa than BDNF for synapse formation?
Dihexa is approximately 10 million times more potent than BDNF at promoting synaptogenesis. This extraordinary potency comes from its picomolar binding affinity for HGF (Kd = 65 pM) and activation of c-Met receptor, enabling profound cognitive effects at very low doses compared to other peptides.
What's the difference between Dihexa and its prodrug Fosgonimeton?
Fosgonimeton is a prodrug form of Dihexa designed for better pharmacokinetics and clinical development. It showed efficacy in Phase I trials for Alzheimer's disease with normalization of P300 latency. Fosgonimeton may be more stable and bioavailable than raw Dihexa, though research is ongoing.
Does Dihexa cause headaches or other side effects like other nootropics?
Yes, headaches are the most common side effect reported with Dihexa use, particularly during initial doses. Anxiety, overstimulation, and sleep disruption can also occur due to its potent neuroplastic effects. Starting at low doses (5mg) and timing away from bedtime may minimize these effects.
Is Dihexa safe to combine with other cognitive-enhancing peptides?
Combining Dihexa with other potent nootropics like Semax or Selank may cause overstimulation or excessive neuroplasticity. Limited human data exists for combinations. If stacking, start conservatively and monitor for increased headaches, anxiety, or mood disturbances indicating neural overstimulation.
References
- 1Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia AgentsMcCoy AT, Benoist CC, Wright JW, Harding JW · Journal of Pharmacology and Experimental Therapeutics · 2013
Oral dihexa (2 mg/kg) completely reversed scopolamine-induced cognitive deficits in Morris water maze by day 7; produced near 3-fold increase in hippocampal dendritic spines at picomolar concentrations.
reviewPubMed 23055539 ↗ - 2The Procognitive and Synaptogenic Effects of Angiotensin IV-Derived Peptides Are Dependent on Activation of the Hepatocyte Growth Factor/c-Met SystemBenoist CC, Kawas LH, Zhu M, Bhatt D, Wright JW, Harding JW · Journal of Pharmacology and Experimental Therapeutics · 2014
Dihexa binds HGF with high affinity (Kd = 65 pM), induces c-Met phosphorylation and hippocampal spinogenesis/synaptogenesis similar to HGF; effects blocked by c-Met inhibitor confirming HGF/c-Met dependence.
reviewPubMed 25187433 ↗ - 3The Development of Small Molecule Angiotensin IV Analogs to Treat Alzheimer's and Parkinson's DiseasesWright JW, Harding JW · Progress in Neurobiology · 2015
Comprehensive review establishing dihexa as an orally active, BBB-permeable compound that facilitates compromised memory and motor systems via HGF/c-Met modulation.
reviewPubMed 25455861 ↗ - 4AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling PathwayGao Y, Zhang Y, Wang Z, et al. · Brain Research Bulletin · 2021
Dihexa restored spatial learning in APP/PS1 Alzheimer's mice, increased neuronal cells and synaptophysin expression, decreased astrocyte/microglia activation, and reduced IL-1B and TNF-a via PI3K/AKT pathway.
animalPubMed 34827486 ↗