Dihexa

Overview

Dihexa is a synthetic derivative of angiotensin IV, developed at Washington State University. It represents one of the most potent cognitive-enhancing compounds discovered, demonstrating remarkable effects on synaptic plasticity and memory formation in preclinical studies.

The compound's extraordinary potency—reported to be 10 million times more potent than BDNF at promoting synaptogenesis—has generated significant research interest, though human studies remain limited.

Structure: N-hexanoic-Tyr-Ile-(6) aminohexanoic amide (modified hexapeptide)

Mechanism of Action

Dihexa's primary mechanism involves the HGF/c-Met system:

HGF/c-Met Pathway Activation

• Potentiates Hepatocyte Growth Factor (HGF) signaling
• Enhances c-Met receptor activation
• Does not directly bind c-Met but facilitates dimerization
• Amplifies endogenous HGF activity

Synaptogenesis

• Promotes formation of new synapses
• Increases dendritic spine density
• Enhances synaptic connectivity
• Effects observed at picomolar concentrations

Neuroplasticity Enhancement

• Augments long-term potentiation (LTP)
• Improves memory consolidation
• Facilitates learning acquisition
• Reverses cognitive deficits in animal models

Neuroprotection

• Protects against scopolamine-induced deficits
• Reduces neurodegeneration markers
• May promote neuronal survival
• Anti-apoptotic effects suggested

Research Summary

Cognitive Enhancement Studies

Spatial Memory (Rat)

• Completely reversed scopolamine-induced deficits
• Enhanced performance in Morris water maze
• Effects at extremely low doses (picomolar)
• Persistent improvements observed

Recognition Memory

• Improved object recognition
• Enhanced novel object exploration
• Effects comparable to or exceeding other nootropics

Potency Comparison

Note: This comparison specifically relates to synaptogenic potency

Animal Model Results

• Restored cognitive function in aged rats
• Reversed chemically-induced cognitive deficits
• Enhanced learning in healthy animals
• Increased dendritic spine density

Key Limitations

• No human clinical trials published
• All data from animal models
• Long-term safety unknown
• Optimal human dosing not established
• HGF system involved in cancer—theoretical concerns

Pharmacokinetics

Note: Human pharmacokinetic data not available

Common Protocols

Note: Dihexa is a research compound with no human clinical trials. The following represents research community protocols, not medical recommendations.

Research Community Protocols

Typical Dosing Ranges:

• 10-30 mg orally, once daily
• 20 mg most commonly reported
• Duration: 2-4 week cycles typical

Administration:

• Oral (primary)
• Sublingual (reported)
• Subcutaneous (less common)

Important Considerations

• Extremely potent—start with lowest doses
• Effects may be cumulative
• Long-term safety unstudied
• Quality and purity critical given potency

Timing

• Once daily dosing common
• Morning administration typical
• Some split into twice daily

Side Effects

Reported (Anecdotal)

Given limited human use data, side effects are poorly characterized:

• Headache
• Fatigue
• Mild anxiety
• Vivid dreams
• "Brain fog" (paradoxically, in some reports)

Theoretical Concerns

HGF/Cancer Connection

• HGF/c-Met pathway involved in cancer progression
• Theoretical concern about promoting existing cancers
• No evidence of carcinogenesis in available data
• Long-term effects unknown

Other Considerations

• Novel compound with limited safety data
• Effects of chronic enhancement of HGF signaling unknown
• Blood-brain barrier penetration may have unintended effects

Interactions

Theoretical Interactions

• Other HGF modulators (unknown)
• Cancer treatments (theoretical concern)
• Other nootropics (unstudied)

Contraindications (Theoretical)

• Known or suspected cancer
• Family history of aggressive cancers
• Pregnancy/nursing
• Under 25 years (brain development ongoing)

Community Insights

Aggregated from research community reports. Given limited data, these should be viewed with significant caution.

Commonly Reported Experiences

• Improved memory and recall
• Enhanced verbal fluency
• Better learning acquisition
• Some report dramatic effects
• Others report subtle or no effects
• Highly variable individual responses

Practical Tips

• Source quality critical given potency
• Start with lowest effective dose
• Monitor for any adverse effects
• Not recommended for long-term continuous use
• Cycle protocols commonly used

Concerns Discussed

• HGF/cancer pathway concerns frequently raised
• Limited human safety data
• High potency requires accurate dosing
• Quality control issues with research chemicals

Why It's Controversial

• Extraordinary claimed potency
• Limited human data despite years since discovery
• Cancer pathway involvement
• Research compound status

References

1. McCoy AT, et al. Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents. J Pharmacol Exp Ther. 2013;344(1):141-54.

2. Benoist CC, et al. Facilitation of hippocampal synaptogenesis and spatial memory by C-terminal truncated Nle1-angiotensin IV analogs. J Pharmacol Exp Ther. 2011;339(1):35-44.

3. Wright JW, Harding JW. The brain hepatocyte growth factor/c-Met receptor system: a new target for the treatment of Alzheimer's disease. J Alzheimers Dis. 2015;45(4):985-1000.

4. Kawas LH, et al. Mimicry of Central Effects of Angiotensin IV: Analogs Modified at the N-terminus. J Pharmacol Exp Ther. 2012;343(1):110-9.

5. Wright JW, et al. Contributions of the Brain Angiotensin IV-AT4 Receptor Subtype System to Spatial Learning. J Neurosci. 1999;19(10):3952-61.