Davunetide vs Dihexa

Stabilizes microtubules by interacting with tubulin and microtubule-associated proteins. Activates SIRT1, reduces amyloid-β toxicity, and enhances synaptic plasticity. Protects against tau hyperphosphorylation.

Davunetide (AL-108; NAP; NAPVSIPQ) is a synthetic octapeptide derived from activity-dependent neuroprotective protein (ADNP), initially identified as a neuroprotective sequence from ADNP and investigated in clinical trials as a candidate treatment for cognitive impairment associated with schizophrenia and tauopathies including progressive supranuclear palsy. Davunetide is proposed to stabilize microtubule dynamics by interacting with tubulin and preventing tau hyperphosphorylation-related cytoskeletal disruption, and preclinical models demonstrated neuroprotective and procognitive effects at nanomolar concentrations. Clinical investigation included Phase 2 trials examining cognitive outcomes and MRS neuroimaging biomarkers in schizophrenia patients, and a Phase 2/3 trial in progressive supranuclear palsy; results showed some neurochemical effects but no consistent meaningful cognitive improvement across clinical endpoints, and the PSP program did not meet its primary outcomes. Davunetide has no FDA approval and no approved indication in any jurisdiction; clinical development has been discontinued following negative trial outcomes, and while its preclinical neuroprotective profile remains scientifically interesting, the clinical evidence does not establish efficacy for cognitive enhancement or neuroprotection in any condition.

HGF/MET receptor potentiator; promotes new synapse formation; estimated 7 orders of magnitude more potent than BDNF in synaptogenesis models

Dihexa is a synthetic small peptide drug candidate developed at Washington State University, proposed to augment cognitive function through potentiation of hepatocyte growth factor (HGF) and MET receptor signaling, a pathway that supports synaptic formation and hippocampal neuroplasticity. The underlying AT4/IRAP receptor system, through which dihexa is proposed to act, has been shown in preclinical rodent studies to enhance long-term potentiation (LTP) in hippocampal tissue and support neuroplastic processes associated with memory formation. Preclinical models have demonstrated memory-enhancing effects following dihexa administration; however, no peer-reviewed human clinical trials have been published as of 2025 and the compound does not appear in indexed biomedical literature under its common name. Dihexa is a research compound with no regulatory approval of any kind; it is not an approved pharmaceutical, and no human safety or pharmacokinetic data has been established. Dihexa administration in research contexts: the compound has been studied in rodent models via oral, intranasal, and subcutaneous routes, with preclinical data suggesting intranasal delivery may offer efficient CNS access due to olfactory pathway absorption. Nasal spray formulations are available through some research compound suppliers on this basis, though the clinical translatability of rodent CNS delivery data to humans has not been established. Dihexa is structurally derived from angiotensin IV and shares the AT4/IRAP receptor pharmacology of its precursor compounds; it is sometimes compared to semax and other nootropic peptides in terms of proposed cognitive mechanism, though its HGF/MET-dependent mechanism is distinct from the ACTH-fragment or NGF-upregulating mechanisms of semax and selank. The cognitive enhancement peptide landscape — and provider availability for researched compounds in this space — is covered in the PeptideBase cognitive peptides directory.