Davunetide
A synthetic ADNP-derived octapeptide investigated as a microtubule-stabilizing neuroprotectant for schizophrenia and tauopathies.
Davunetide (AL-108; NAP; NAPVSIPQ) is a synthetic octapeptide derived from activity-dependent neuroprotective protein (ADNP), first identified as a neuroprotective sequence and advanced into human trials for cognitive impairment in schizophrenia and for tauopathies such as progressive supranuclear palsy. It is proposed to stabilize microtubule dynamics by interacting with tubulin and to limit tau hyperphosphorylation-related cytoskeletal disruption, with preclinical models showing procognitive and neuroprotective effects at nanomolar concentrations. Despite an interesting preclinical profile, clinical trials did not produce consistent, meaningful cognitive improvement and the progressive supranuclear palsy program failed its primary endpoints; development has since been discontinued.
Class
Synthetic octapeptide (ADNP-derived neuroprotective fragment)
Routes
Intranasal, Subcutaneous
Category
Cognitive & Nootropic
Researched benefits
What it's studied for
Microtubule stabilization
Interacts with tubulin and microtubule-associated proteins to stabilize microtubule dynamics, the structural basis proposed for its neuroprotective actions in preclinical models.
Tau pathology protection
Proposed to reduce tau hyperphosphorylation and the resulting cytoskeletal disruption, the rationale behind its investigation in tauopathies such as progressive supranuclear palsy.
Neuronal integrity biomarkers
In an MRS substudy in schizophrenia, higher-dose davunetide was associated with higher N-acetylaspartate and choline signals in dorsolateral prefrontal cortex, markers consistent with neuronal membrane integrity and myelin preservation.
Functional capacity in schizophrenia
In a 12-week trial, intranasal davunetide produced a significant beneficial effect on performance-based functional capacity (UPSA), though standardized cognitive battery scores did not reach significance.
Amyloid and synaptic effects (preclinical)
Preclinical work reports activation of SIRT1, reduced amyloid-beta toxicity, and enhanced synaptic plasticity at nanomolar concentrations.
Mechanism
How it works
Davunetide is the eight-residue peptide NAPVSIPQ, a fragment of activity-dependent neuroprotective protein (ADNP). Its core proposed mechanism is stabilization of microtubule dynamics through interaction with tubulin and microtubule-associated proteins, which supports axonal transport and neuronal cytoskeletal integrity under stress.
By stabilizing microtubules, davunetide is thought to protect against tau hyperphosphorylation-related cytoskeletal disruption. This tau-directed rationale is the basis for its testing in tauopathies including progressive supranuclear palsy, where microtubule destabilization and pathological tau are central features.
Additional preclinical mechanisms reported include activation of SIRT1, reduction of amyloid-beta toxicity, and enhancement of synaptic plasticity. In cellular and animal models these actions manifest at nanomolar concentrations, producing neuroprotective and procognitive effects.
In human imaging studies, higher-dose davunetide was linked to increased N-acetylaspartate and choline-to-creatine ratios in the dorsolateral prefrontal cortex, neurochemical signals interpreted as consistent with preserved neuronal membrane integrity and myelin, though these biomarker effects did not translate into consistent clinical cognitive benefit.
Dosing protocols
Dosing & administration
Dosing reflects protocols reported in research and community literature for educational purposes. It is not medical advice or a recommendation. Most peptides here are not approved for human use.
Clinical (schizophrenia trial, low dose)
- Dose
- 5 mg
- Frequency
- Per trial regimen
- Timing
- As administered in study
- Duration
- 12 weeks
- Route
- Intranasal
The 5 mg intranasal dose was well tolerated and associated with a significant effect on performance-based functional capacity (UPSA).
Clinical (schizophrenia trial, high dose)
- Dose
- 30 mg
- Frequency
- Per trial regimen
- Timing
- As administered in study
- Duration
- 12 weeks
- Route
- Intranasal
The 30 mg intranasal dose was well tolerated; the high-dose group showed higher NAA/choline neurochemical biomarkers in an MRS substudy.
- No standardized or approved dosing exists; davunetide is investigational and clinical development has been discontinued.
- Human trials used intranasal administration; subcutaneous is also listed as a route in research contexts.
- Clinical trial doses (5 mg and 30 mg intranasal) are reported for reference only and do not represent an approved regimen.
Evidence
Research & clinical studies (3)
Microtubule-stabilizing drugs suppress convulsions in a C. elegans model of CAMSAP disorders
Microtubule-stabilizing drugs suppressed convulsions in a C. elegans model of CAMSAP disorders, suggesting microtubule stabilization as a therapeutic approach for associated seizures.
PMID 41955672Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia
In an 18-participant MRS substudy, the high-dose group showed a trend toward 8.0% higher N-acetylaspartate and a significant 7.9% higher choline-to-creatine ratio in dorsolateral prefrontal cortex at 12 weeks, consistent with a neuroprotective mechanism.
PMID 23325325Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia
In a 12-week multicenter double-blind trial (n=63), intranasal davunetide at 5 mg and 30 mg was well tolerated and produced a significant beneficial effect on performance-based functional capacity (UPSA; d=0.74 for 5 mg), though MATRICS cognitive battery changes did not reach significance.
PMID 22169248Safety
Side effects & considerations
Commonly reported effects
Contraindications & cautions
- Pregnant or nursing
Davunetide was reported as well tolerated in schizophrenia trials at both 5 mg and 30 mg intranasal doses. It is considered lower risk in research contexts, but individual response varies and it remains an investigational compound with no approved use.
FAQ
Davunetide — common questions
What is Davunetide?
Davunetide (AL-108; NAP; NAPVSIPQ) is a synthetic octapeptide derived from activity-dependent neuroprotective protein (ADNP). It was identified as a neuroprotective sequence and investigated in clinical trials as a candidate treatment for cognitive impairment in schizophrenia and for tauopathies including progressive supranuclear palsy.
How does Davunetide work?
It is proposed to stabilize microtubule dynamics by interacting with tubulin, limiting tau hyperphosphorylation-related cytoskeletal disruption. Preclinical work also reports SIRT1 activation, reduced amyloid-beta toxicity, and enhanced synaptic plasticity at nanomolar concentrations.
What is Davunetide primarily studied for?
Neuroprotection, tau stabilization, cognitive enhancement, memory, and synaptic plasticity.
Does Davunetide improve cognition in humans?
Clinical trials showed some neurochemical effects and a benefit on performance-based functional capacity in schizophrenia, but no consistent, statistically significant improvement across standardized cognitive endpoints. The progressive supranuclear palsy program did not meet its primary outcomes.
What are the side effects of Davunetide?
It was generally well tolerated in trials. Reported considerations include avoiding use if pregnant or nursing. This is educational information only, not medical advice.
Is Davunetide approved or available?
No. Davunetide has no FDA approval and no approved indication anywhere. Clinical development was discontinued after negative trial results, and it remains an investigational, research-only compound.
How was Davunetide administered in studies?
Human trials used intranasal administration at 5 mg and 30 mg doses over 12 weeks; subcutaneous is also listed as a research route.
